Pyrimidinediamine kinase inhibitors

ABSTRACT

Disclosed embodiments provide pyrimidinediamine compounds useful for inhibiting kinase activity, including the activity of polo-like kinase 1 (PLK1). Also disclosed are pharmaceutical compositions comprising these compounds and methods of treating diseases associated with kinase activity, in particular enhanced PLK1 catalytic activity, such as diseases associated with abnormal cell proliferation, including neoplastic disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/649,073, filed on Dec. 29, 2009, which claims the benefit of theearlier filing date of U.S. Provisional Application Ser. No. 61/141,635,filed Dec. 30, 2008, both of which prior applications are incorporatedherein by reference.

FIELD

The present invention relates generally to 2,4-pyrimidinediaminecompounds that inhibit kinases, in particular polo-like kinase 1 (PLK1),pharmaceutical compositions which include the compounds, and methods ofusing the compounds and compositions for treatment of a variety ofdiseases and conditions associated with enhanced PLK1 activity,including hyperproliferative disorders.

BACKGROUND

Human polo-like kinase 1 (human PLK1) is a Serine/Threonine kinase,which belongs to a PLK family, named after a structurally similar polokinase from Drosophila melanogaster. Drosophila polo mutants aredefective in mitosis and have abnormal mitotic spindle poles. Inmammals, four structurally homologous PLK proteins (PLK1, PLK2, PLK3,and PLK4) have been identified to date, all of them sharing a commonarchitecture and having an N-terminal kinase catalytic domain and aC-terminal region containing either one (PLK4) or two (PLK1, PLK2, PLK3)polo-box domains PLK1 is the most studied and best characterized memberof the family. Specifically, PLK1 recapitulates most of the functions ofpolo kinase and is known to be a key regulator of mitosis in humancells.

PLK1 expression level and activity are strongly cell-cycle regulated,and peak around the time the cell enters into mitotic phase.Importantly, PLK1 transcripts are found only in proliferating tissues,while PLK2 (Serum-inducible kinase, SNK) and PLK3(Proliferation-related, fibroblast growth factor inducible kinase, FNK)transcripts have broad tissue distribution, including post-mitoticneurons. PLK4/SAK is believed to function mostly in centriolebiogenesis, and, like PLK1, is essential for cell viability.

PLK1 is essential for normal mitotic progression, and functions atmultiple steps of mitosis. Specifically, PLK1 is necessary for entryinto mitosis, for centrosomal maturation, mitotic spindle assembly andmaintenance, exit from mitosis and for cytokinesis. At each of thesesteps PLK1 phosphorylates a distinct set of substrate proteins. Beforeentry into mitosis PLK1 phosphorylates and activates phosphatase cdc25c,which then translocates to the nucleus and, in turn, removes inhibitoryphosphates from cyclin-dependent kinase CDK1. PLK1 also phosphorylatescyclin B1, the partner of CDK1. Together, activated CDK1/cyclin Bcomplex initiates entry of the cell into mitosis.

PLK1 overexpression is believed to be strongly associated withneoplastic cells. Specifically, it has been shown that PLK1 RNA isexpressed at high levels in lung and breast tumors, with little to noexpression in adjacent normal tissue. Further, PLK1 overexpression wasfound to correlate with histological grade, and poor prognosis inseveral types of cancer, such as ovarian and endometrial cancers,esophageal carcinomas and non-small cell lung carcinomas.

Downregulation of PLK1 in tumor cells induces mitotic arrest andsubsequent cell death. Therefore what is needed are compounds andcompositions that inhibit PLK1 for use in treatment of disease stateswhere the PLK1 pathway is involved.

SUMMARY

Aspects of the present disclosure relate to pyrimidinediamine compoundswhich are useful as kinase inhibitors. In particular, representativecompounds include PLK1 inhibitors Also disclosed herein are methods forusing these compounds in treating diseases and conditions associatedwith a kinase activity and in particular, enhanced PLK1 activity, suchas hyperproliferative disorders, including neoplasms, and pharmaceuticalcompositions which include these compounds.

In one aspect, provided herein is a compound according to Formula I:

or a pharmaceutically acceptable salt, a solvate, an N-oxide, or aprodrug thereof,

wherein:

Y¹ is O or S;

Z¹ is CH or N;

A is an aromatic ring;

R¹ is H;

R² and R³ are each, independently of one another, H, (C1-C6) alkyloptionally substituted with one or more of the same or different R¹¹groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R¹¹ groups, (C4-C11) cycloalkylalkyl optionallysubstituted with one or more of the same or different R¹¹ groups,(C5-C10) aryl optionally substituted with one or more of the same ordifferent R¹¹ groups, (C6-C16) arylalkyl optionally substituted with oneor more of the same or different R¹¹ groups, 2-6 membered heteroalkyloptionally substituted with one or more of the same or different R¹¹groups, 3-8 membered cycloheteroalkyl, optionally substituted with oneor more of the same or different R¹¹ groups, 4-11 memberedcycloheteroalkylalkyl, optionally substituted with one or more of thesame or different R¹¹ groups, 5-10 membered heteroaryl optionallysubstituted with one or more of the same or different R¹¹ groups or 6-16membered heteroarylalkyl optionally substituted with one or more of thesame or different R¹¹ groups;

In one embodiment, R², R³, or both independently are phosphate esterprogroups. Examples of such progroups have the formula—(CR^(d)R^(d))_(y)—O—P(O)(OH)(OR^(e)) or—(CR^(d)R^(d))_(y)—O—P(O)(OR^(e))(OR^(e)), or a salt thereof, whereineach R^(e) is, independently of the others, selected from substituted orunsubstituted lower alkyl, substituted or unsubstituted (C6-C14) aryl(e.g., phenyl, naphthyl, 4-lower alkoxyphenyl, 4-methoxyphenyl),substituted or unsubstituted (C7-C20) arylalkyl (e.g., benzyl,1-phenylethan-1-yl, 2-phenylethan-1-yl), —(CR^(d)R^(d))_(y)—OR^(f),—(CR^(d)R^(d))_(y)—O—C(O)R^(f), —(CR^(d)R^(d))_(y)—O—C(O)OR^(f),—(CR^(d)R^(d))_(y)—S—C(O)R^(f), —(CR^(d)R^(d))_(y)—S—C(O)OR^(f),—(CR^(d)R^(d))_(y)—NH—C(O)R^(f), —(CR^(d)R^(d))_(y)—NH—C(O)OR^(f) and—Si(R^(d))₃, wherein R^(d), R^(f) and y are as defined above. In aspecific embodiment, each R^(d) is selected from hydrogen andunsubstituted lower alkyl and/or each R^(e) is an unsubstituted loweralkanyl or benzyl. Specific exemplary phosphate ester progroups include,but are not limited to, —CH₂—O—P(O)(OH)(OR^(e)),—CH₂CH₂—O—P(O)(OH)(OR^(e)), —CH₂—O—P(O)(OR^(e))(OR^(e)) and—CH₂CH₂—O—P(O)(OR^(e))(OR^(e)), where R^(e) is selected from loweralkanyl, i-propyl and t-butyl.

In other embodiments, R², R³, or both independently may be cyclicphosphate ester-containing progroups of the formula

wherein each R^(g) is, independently of the others, selected fromhydrogen and lower alkyl; each R^(h) is, independently of the others,selected from hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted lower cycloheteroalkyl, substituted orunsubstituted (C6-C14) aryl, substituted or unsubstituted (C7-C20)arylalkyl and substituted or unsubstituted 5-14 membered heteroaryl; zis an integer ranging from 0 to 2; and R^(d) and y are as previouslydescribed. In a specific embodiment, a phosphate ester-containingprogroup R², R³, or both is a cyclic phosphate ester of the formula

where R^(d), R^(h) and y are as previously defined.

Without being limited to any particular theory of operation, themechanism by which cyclic phosphate ester prodrugs including such cyclicphosphate ester progroups metabolize in vivo to the active drug compounddepends, in part, on the identity of the R^(h) substituent. For example,cyclic phosphate ester progroups in which each R^(h) is, independentlyof the others, selected from hydrogen and lower alkyl are cleaved invivo by esterases. Thus, in some embodiments, the cyclic phosphate esterprogroups are selected such that they are cleavable in vivo byesterases. Specific examples of such cyclic phosphate ester progroupsinclude, but are not limited to, progroups selected from

Alternatively, cyclic phosphate ester prodrugs having progroups in whichthe R^(h) substituents are substituted or unsubstituted aryl, arylalkyland heteroaryl groups, are not typically cleaved by esterases, but areinstead metabolized to the active prodrug by enzymes, such as cytochromeP₄₅₀ enzymes, that reside in the liver. For example, a series of cyclicphosphate ester nucleotide prodrugs that undergo an oxidative cleavagereaction catalyzed by a cytochrome P₄₅₀ enzyme (CYP) expressedpredominantly in the liver are described in Erion et al., 2004, J. Am.Chem. Soc. 126:5154-5163. In some embodiments, the cyclic phosphateester progroups are selected such that they are cleavable by CYP enzymesexpressed in the liver. Specific exemplary embodiments of such cyclicphosphate ester-containing progroups include, but are not limited to,progroups having the formula

where R^(h) is selected from phenyl, 3-chlorophenyl, 4-pyridyl and4-methoxyphenyl;

R⁴ and R⁵ are each, independently of one another, H, (C1-C6) alkyl,(C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, (C1-C6) haloalkoxy, (C1-C6)aminoalkyl or (C1-C6) hydroxyalkyl; or, alternatively, R⁴ and R⁵, takentogether with the carbon atom to which they are bonded, form aspirocycloalkyl or a spirocycloheteroalkyl, or, alternatively, R⁴ andR⁵, taken together with the carbon atom to which they are bonded, form aC═O group;

R⁶ and R⁷ are each, independently of one another, H, (C1-C6) alkyl,(C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, (C1-C6) haloalkoxy, (C1-C6)aminoalkyl or (C1-C6) hydroxyalkyl; or, alternatively, R⁶ and R⁷, takentogether with the carbon atom to which they are bonded, form aspirocycloalkyl or a spirocycloheteroalkyl or, alternatively, R⁶ and R⁷,taken together with the carbon atom to which they are bonded, form a C═Ogroup;

R⁸ is H, halo, (C1-C6) alkyl optionally substituted with one or more ofthe same or different R¹¹ groups, (C1-C3) haloalkyloxy, —OR^(d),—SR^(d), —NR^(c)R^(c), (C1-C3) haloalkyl, —C(O)OR^(d), —CN, —NC, —OCN,—SCN, —NO or —NO₂;

two R⁹, taken together with the nitrogen atom to which they are bonded,form a 4- to 8-membered monocyclic cycloheteroalkyl, 6- to 10-memberedbridged bicyclic cycloheteroalkyl, or 6- to 12-membered bridgedtricyclic cycloheteroalkyl, wherein each may optionally be substitutedwith one or more of the same or different R¹¹ groups, and wherein thesubstituted or unsubstituted mono-, bi- or tricyclic cycloheteroalkylincludes at least two nitrogen atoms;

each R¹⁰ is independently R¹¹ or alternatively, two R¹⁰ on vicinalcarbons, taken together with the carbons to which they are bonded, forma ring fused to A, where the ring fused to A is a 5- to 8-memberedcycloalkyl, a 5- to 8-membered cycloheteroalkyl, 5- to 6-membered arylor a 5- to 6-membered heteroaryl, each optionally substituted with oneor more of the same or different R¹¹ groups;

each R¹¹ is independently H, R^(e), R^(b), R^(e) substituted with one ormore of the same or different R^(a) and/or R^(b), —OR^(e) substitutedwith one or more of the same or different R^(a) and/or R^(b), —SR^(e)substituted with one or more of the same or different R^(a) and/orR^(b), —C(O)R^(e) substituted with one or more of the same or differentR^(a) and/or R^(b), —N(R^(a))R^(e) where R^(e) is substituted with oneor more of the same or different R^(a) and/or R^(b), —S(O)₂R^(e)substituted with one or more of the same or different R^(a) and/orR^(b), —N(R^(a))—S(O)₂R^(e) where R^(e) is substituted with one or moreof the same or different R^(a) and/or R^(b), —B(OR^(a))₂,—B(N(R^(c))₂)₂, —(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(a))₂)_(m)—R^(b),—S—(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(b))₂)_(m)—R^(a),—N(R^(a))—(C(R^(a))₂)_(m)—R^(b), —O—(CH₂)_(m)—CH((CH₂)_(m)R^(b))R^(b),—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—O—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—N((C(R^(a))₂)_(m)R^(b))₂,—S—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—N(R^(a))—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—N(R^(a))—C(O)—(C(R^(a))₂)_(m)—C(R^(a))(R^(b))₂ or—N(R^(a))—(C(R^(a))₂)_(m)—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b);

each R^(a) is independently H, deuterium, (C1-6)alkyl, (C3-8)cycloalkyl,(C4-11)cycloalkylalkyl, (C6-10)aryl, (C7-16)arylalkyl, 2-6 memberedheteroalkyl, 3-10 membered heteroalicyclyl, 4-11 memberedheteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 memberedheteroarylalkyl;

each R^(b) is independently ═O, —OR^(a), —O—(C(R^(a))₂), —OR^(a),(C1-3)haloalkyloxy, —OCF₃, ═S, —SR^(a), ═NR^(a), ═NOR^(a), —N(R^(c))₂,halo, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a),—S(O)₂R^(a), —SO₃R^(a), —S(O)N(R^(c))₂, —S(O)₂N(R^(c))₂, —OS(O)R^(a),—OS(O)₂R^(a), —OSO₃R^(a), —OS(O)₂N(R^(c))₂, —C(O)R^(a), —CO₂R^(a),—C(O)N(R^(c))₂, —C(NR^(a))—N(R^(c))₂, —C(NOH)—R^(a), —C(NOH)—N(R^(c))₂,—OC(O)R^(a), —OC(O)OR^(a), —OC(O)N(R^(c))₂, —OC(NH)—N(R^(c))₂,—OC(NR^(a))—N(R^(c))₂, —N(R^(a))—S(O)₂H, —[N(R^(a))C(O)]_(n)R^(a),—[N(R^(a))C(O)_(n)]OR^(a), —[N(R^(a))C(O)]_(n)N(R^(c))₂ or—[N(R^(a))C(NR^(a))]_(n)—N(R^(c))₂;

each R^(c) is independently R^(a), or, alternatively, two R^(c) aretaken together with the nitrogen atom to which they are bonded to form a3 to 10-membered heteroalicyclyl or a 5-10 membered heteroaryl which mayoptionally include one or more of the same or different additionalheteroatoms and which is optionally substituted with one or more of thesame or different R^(a) and/or R^(d) groups;

each R^(d) is ═O, —OR^(a), —OCF₃, ═S, —SR^(a), ═NR^(a), ═NOR^(a),—N(R^(a))₂, halo, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃,—S(O)R^(a), —S(O)₂R^(a), —SO₃R^(a), —S(O)N(R^(a))₂, —S(O)₂N(R^(a))₂,—OS(O)R^(a), —OS(O)₂R^(a), —OSO₃R^(a), —OS(O)₂N(R^(a))₂, —C(O)R^(a),—CO₂R^(a), —C(O)N(R^(a))₂, —C(NR^(a))N(R^(a))₂, —C(NOH)R^(a),—C(NOH)N(R^(a))₂, —OCO₂R^(a), —OC(O)N(R^(a))₂, —OC(NR^(a))N(R^(a))₂,—[N(R^(a))C(O)]_(n)R^(a), —(C(R^(a))₂)_(n)—OR^(a), —N(R^(a))—S(O)₂R^(a),—C(O)—(C1-6)haloalkyl, —S(O)₂—(C1-6)haloalkyl, —OC(O)R^(a),—O(C(R^(a))₂)_(m)—OR^(a), —S(C(R^(a))₂)_(m)—OR^(a),—N(R^(a))—(C1-6)haloalkyl, —P(O)(OR^(a))₂,—N(R^(a))—(C(R^(a))₂)_(m)—OR^(a), —[N(R^(a))C(O)]_(n)OR^(a),—[N(R^(a))C(O)]_(n)N(R^(a))₂, —[N(R^(a))C(NR^(a))]_(n)N(R^(a))₂ or—N(R^(a))C(O)(C1-6)haloalkyl; two R^(d), taken together with the atom oratoms to which they are attached, combine to form a 3-10 memberedpartially or fully saturated mono or bicyclic ring, optionallycontaining one or more heteroatoms and optionally substituted with oneor more R^(a);

each R^(e) is independently (C1-6)alkyl, (C3-8)cycloalkyl,(C4-11)cycloalkylalkyl, (C6-10)aryl, (C7-16)arylalkyl, 2-6 memberedheteroalkyl, 3-10 membered heteroalicyclyl, 4-11 memberedheteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 memberedheteroarylalkyl;

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3;

provided the compound is not:

-   N4-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;-   4-{3-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid methyl ester;-   N4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-[3-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;-   4-{3-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   1-(4-{3-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone;-   6-{5-Fluoro-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   6-{2-[3-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   4-{3-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   6-{5-Fluoro-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   6-{2-[3-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   4-{3-[5-Fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   N4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;-   N2-[3-Chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-N4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-pyrimidine-2,4-diamine;-   N4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;-   4-{4-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   1-(4-{4-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone;-   4-{4-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   4-{4-[5-Fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   6-{5-Fluoro-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   6-{5-Fluoro-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   6-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   4-{4-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid methyl ester;-   4-{4-[5-Fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid methyl ester; or-   6-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one.

In another aspect, the compound of Formula I is provided, wherein twoR⁹, taken together with the nitrogen atom to which they are bonded, forma 6- to 10-membered bridged bicyclic cycloheteroalkyl, which may beoptionally substituted with one or more of the same or different R¹¹groups, and wherein the substituted or unsubstituted bridged bicycliccycloheteroalkyl includes at least two nitrogen atoms.

In yet another aspect, a pharmaceutical composition is provided, whichincludes a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of one or more of the pyrimidinediamine compoundsprovided herein, including pharmaceutically acceptable salts, solvates,and prodrugs thereof, e.g., a compound of Formula I. The exact nature ofthe carrier will depend upon the desired use for the composition, andmay range from being suitable or acceptable for veterinary uses to beingsuitable or acceptable for human use.

The pyrimidinediamine compounds provided herein are potent inhibitors ofPLK1 in in vitro assays. Accordingly, in yet another aspect, a method oftreating a disease or condition associated with enhanced PLK1 catalyticactivity in a mammal is provided. The method includes administering to amammal in need thereof, a therapeutically effective amount of one ormore of the pyrimidinediamine compounds disclosed herein, includingpharmaceutically acceptable salts, solvates, prodrugs, and compositionsthereof, e.g., a compound of Formula I disclosed above.

In yet another aspect, use of one or more of the pyrimidinediaminecompounds disclosed herein, including pharmaceutically acceptable salts,solvates, and prodrugs thereof, in the manufacture of a medicament fortreatment of a disease or condition associated with enhanced PLK1catalytic activity, is provided.

In some embodiments, the disease or condition associated with enhancedPLK1 catalytic activity is a disease or condition associated withabnormal cell proliferation, e.g., a cancer or a neoplasm.

Examples of such diseases include without limitation leukemia, lymphoma(Hodgkin's and non-Hodgkin's), malignancies of the brain, bladder,breast, colon, lung, ovaries, pancreas, prostate, skin, and uterus,including solid tumors, such as carcinomas and sarcomas, as well asother proliferative conditions, such as benign tumors.

In certain embodiments, a method of inhibiting proliferation of a cellis provided, the method including contacting the cell with an effectiveamount of one or more of the pyrimidinediamine compounds disclosedherein, including pharmaceutically acceptable salts, solvates, andprodrugs thereof.

DETAILED DESCRIPTION

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated branched, or straight-chain acyclic monovalenthydrocarbon radical having the stated number of carbon atoms (i.e.,C1-C6 means one to six carbon atoms) that is derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkeneor alkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, but-1-en-1-yl,but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl, but-1-yn-3-yl,but-3-yn-1-yl, and the like. Where specific levels of saturation areintended, the nomenclature “alkanyl,” “alkenyl” and/or “alkynyl” isused, as defined below. In some embodiments, the alkyl groups are(C1-C6) alkyl.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched or straight-chain acyclic alkyl derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl and propan-2-yl(isopropyl); butanyls such as butan-1-yl, butan-2-yl (sec-butyl),2-methyl-propan-1-yl(isobutyl), 2-methyl-propan-2-yl (t-butyl), etc.,and the like. In some embodiments, the alkanyl groups are (C1-C6)alkanyl.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched or straight-chain acyclic alkyl having at least onecarbon-carbon double bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkene. The group may be in eitherthe cis or trans conformation about the double bond(s). Typical alkenylgroups include, but are not limited to, ethenyl; propenyls such asprop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl; butenylssuch as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,and the like. In some embodiments, the alkenyl group is (C2-C6) alkenyl.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched or straight-chain acyclic alkyl having at least onecarbon-carbon triple bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkyne. Typical alkynyl groupsinclude, but are not limited to, ethynyl; propynyls such asprop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, and the like. In some embodiments, thealkynyl group is (C2-C6) alkynyl.

“Alkyldiyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic divalenthydrocarbon group having the stated number of carbon atoms (i.e., C1-C6means from one to six carbon atoms) derived by the removal of onehydrogen atom from each of two different carbon atoms of a parentalkane, alkene or alkyne, or by the removal of two hydrogen atoms from asingle carbon atom of a parent alkane, alkene or alkyne. The twomonovalent radical centers or each valency of the divalent radicalcenter can form bonds with the same or different atoms. Typicalalkyldiyl groups include, but are not limited to, methandiyl; ethyldiylssuch as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl;propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl,propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl,prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl,prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl,cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as,butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl,buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl,cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl,but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, and thelike. Where specific levels of saturation are intended, the nomenclaturealkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Where it isspecifically intended that the two valencies are on the same carbonatom, the nomenclature “alkylidene” is used. In preferred embodiments,the alkyldiyl group is (C1-C6) alkyldiyl. Also preferred are saturatedacyclic alkanyldiyl groups in which the radical centers are at theterminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl (ethano);propan-1,3-diyl (propano); butan-1,4-diyl (butano); and the like (alsoreferred to as alkylenos, defined infra).

“Alkyleno” by itself or as part of another substituent refers to astraight-chain saturated or unsaturated alkyldiyl group having twoterminal monovalent radical centers derived by the removal of onehydrogen atom from each of the two terminal carbon atoms ofstraight-chain parent alkane, alkene or alkyne. The location of a doublebond or triple bond, if present, in a particular alkyleno is indicatedin square brackets. Typical alkyleno groups include, but are not limitedto, methano; ethylenos such as ethano, etheno, ethyno; propylenos suchas propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenossuch as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno,but[2]yno, buta[1,3]diyno, and the like. Where specific levels ofsaturation are intended, the nomenclature alkano, alkeno and/or alkynois used. In preferred embodiments, the alkyleno group is (C1-C6) or(C1-C3) alkyleno. Also preferred are straight-chain saturated alkanogroups, e.g., methano, ethano, propano, butano, and the like.

A “bivalent linker” refers to a straight-chain or branched moiety whichmay be cyclic or acyclic that is capable of forming two bonds to theatoms that are to be linked. The bonds can originate from one atom, twovicinal atoms, or two terminal atoms. Examples of bivalent linkersinclude without limitation alkyldyil and alkyleno linkers, as well asbivalent aryls, heteroaryls, heteroalkyl, etc.

“Heteroalkyl,” “Heteroalkanyl,” “Heteroalkenyl,” “Heteroalkynyl,”“Heteroalkyldiyl” and “Heteroalkyleno” by themselves or as part ofanother substituent refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyland alkyleno groups, respectively, in which one or more of the carbonatoms are each independently replaced with the same or differentheteroatoms or heteroatomic groups. Typical heteroatoms and/orheteroatomic groups which can replace the carbon atoms include, but arenot limited to, —O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)₂—,—S(O)NR′—, —S(O)₂NR′—, and the like, including combinations thereof,where each R′ is independently hydrogen, (C1-C6) alkyl, or asspecifically defined.

“Cycloalkyl” and “Heterocycloalkyl” (or “Cycloheteroalkyl”) bythemselves or as part of another substituent refer to cyclic versions of“alkyl” and “heteroalkyl” groups, respectively, including monycyclic,bicyclic, and tricyclic systems. For heteroalkyl groups, a heteroatomcan occupy the position that is attached to the remainder of themolecule. Typical cycloalkyl groups include, but are not limited to,cyclopropyl; cyclobutyls such as cyclobutanyl and cyclobutenyl;cyclopentyls such as cyclopentanyl and cyclopentenyl; cyclohexyls suchas cyclohexanyl and cyclohexenyl; bicyclic groups such as decalinyl, andnorbornyl, and tricyclic groups such as adamantyl and the like. Typicalheterocycloalkyl groups include, but are not limited to,tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,etc.), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, etc.),morpholinyl (e.g., morpholin-3-yl, morpholin-4-yl, etc.), piperazinyl(e.g., piperazin-1-yl, piperazin-2-yl, etc.),1,4-diazabicyclo-[2.2.2]octanyl, and the like.

“Bridged bicyclic heterocycloalkyl (or cycloheteroalkyl)” by itself oras part of another substituent refers to a bicyclic cycloalkyl,containing at least one bridge atom between two bridgehead atoms, whereone or more of the carbon atoms are each independently replaced with thesame or different heteroatoms or heteroatomic groups. Typicalheteroatoms and/or heteroatomic groups which can replace the carbonatoms include, but are not limited to, —O—, —S—, —S—O—, —NR′—, —PH—,—S(O)—, —S(O)₂—, —S(O)NR′—, —S(O)₂NR′—, and the like, includingcombinations thereof, where each R′ is independently hydrogen, (C1-C6)alkyl, or as specifically defined. “Bridged bicyclic cycloheteroalkyl”is a type of “heterocycloalkyl”. Examples of geometries of bridgedbicyclic heteroalkyls include without limitation [3.3.3], [3.3.2],[3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1]. Examples of bridgedbicyclic cycloheteroalkyls containing two nitrogen atoms include withoutlimitation:

wherein R^(f) and R^(g) are each independently H, C1-C6 alkyl, or asspecifically defined.

“Bridged tricyclic cycloheteroalkyl (or cycloheteroalkyl)” by itself oras part of another substituent refers to a tricyclic cycloalkyl,containing at least one bridge atom between two bridgehead atoms, whereone or more of the carbon atoms are each independently replaced with thesame or different heteroatoms or heteroatomic groups. Typicalheteroatoms and/or heteroatomic groups which can replace the carbonatoms include, but are not limited to, —O—, —S—, —S—O—, —NR′—, —PH—,—S(O)—, —S(O)₂—, —S(O)NR′—, —S(O)₂NR′—, and the like, includingcombinations thereof, where each R′ is independently hydrogen, (C1-C6)alkyl, or as specifically defined. “Bridged bicyclic cycloheteroalkyl”is a type of “heterocycloalkyl”. Examples of bridged bicyclicheteroalkyls containing two nitrogen atoms include all-bridged ringsystems like diazaadamantyls, and bridged-fused ring systems, forexample:

“Spirocycloalkyl and spirocycloheteroalkyl (or spiroheterocycloalkyl)”by itself or as part of another substituent refers to a polycyclic(e.g., bicyclic) cycloalkyl or heterocycloalkyl, or one cycle thereof,which contains a single quartenary carbon atom as a connection pointbetween at least two rings. Spirocycloalkyl and spirocycloheteroalkylmay in fact describe the same ring system, e.g. a piperidine ring in aspirocyclic arrangement with the cyclohexane, as for example in theformula:

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon group having the stated number of carbonatoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like, as well as thevarious hydro isomers thereof. In some embodiments, the aryl group is(C5-C15) aryl, such as (C5-C10) aryl. In some embodiments, preferredaryls are cyclopentadienyl, phenyl and naphthyl.

“Arylalkyl” by itself or as part of another substituent refers to analkyl group in which one of the hydrogen atoms bonded to a carbon atom,typically a terminal or sp³ carbon atom, is replaced with an aryl group.Typical arylalkyl groups include, but are not limited to, benzyl,2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylalkenyl and/orarylalkynyl is used. In some embodiments, the arylalkyl group is(C6-C21) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C1-C6) and the aryl moiety is (C5-C15). In someembodiments the arylalkyl group is (C6-C13), e.g., the alkanyl, alkenylor alkynyl moiety of the arylalkyl group is (C1-C3) and the aryl moietyis (C5-C10).

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylalkenyl and/orheteroarylalkynyl is used. In some embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C1-C6) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In some embodiments,the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety is (C1-C3) alkyl and the heteroarylmoiety is a 5-10 membered heteroaryl.

“Halogen” or “Halo” by themselves or as part of another substituent,unless otherwise stated, refer to fluoro, chloro, bromo and iodo.

“Haloalkyl” by itself or as part of another substituent refers to analkyl group in which one or more of the hydrogen atoms is replaced witha halogen. Thus, the term “haloalkyl” is meant to includemonohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls.For example, the expression “(C1-C2) haloalkyl” includes fluoromethyl,difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl,1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.

The above-defined groups may include prefixes and/or suffixes that arecommonly used in the art to create additional well-recognizedsubstituent groups. As examples, “alkyloxy” or “alkoxy” refers to agroup of the formula —OR″, “alkylamine” refers to a group of the formula—NHR″ and “dialkylamine” refers to a group of the formula —NR″R″, whereeach R¹¹ is independently an alkyl. As another example, “haloalkoxy” or“haloalkyloxy” refers to a group of the formula —OR″′, where R″′ is ahaloalkyl.

“Prodrug” refers to a derivative of an active 2,4-pyrimidinediaminecompound (drug) that requires a transformation under the conditions ofuse, such as within the body, to release the active2,4-pyrimidinediamine drug. Prodrugs are frequently, but notnecessarily, pharmacologically inactive until converted into the activedrug. Prodrugs are typically obtained by masking a functional group inthe 2,4-pyrimidinediamine drug believed to be in part required foractivity with a progroup (defined below) to form a promoiety whichundergoes a transformation, such as cleavage, under the specifiedconditions of use to release the functional group, and hence the active2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceedspontaneously, such as by way of a hydrolysis reaction, or it may becatalyzed or induced by another agent, such as by an enzyme, by light,by acid or base, or by a change of or exposure to a physical orenvironmental parameter, such as a change of temperature. The agent maybe endogenous to the conditions of use, such as an enzyme present in thecells to which the prodrug is administered or the acidic conditions ofthe stomach, or it may be supplied exogenously.

A wide variety of progroups, as well as the resultant promoieties,suitable for masking functional groups in the active2,4-pyrimidinediamines compounds to yield prodrugs are well-known in theart. For example, a hydroxyl functional group may be masked as asulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivoto provide the hydroxyl group. An amino functional group may be maskedas an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenylpromoiety, which may be hydrolyzed in vivo to provide the amino group. Acarboxyl group may be masked as an ester (including silyl esters andthioesters), amide or hydrazide promoiety, which may be hydrolyzed invivo to provide the carboxyl group. Other specific examples of suitableprogroups and their respective promoieties will be apparent to those ofskill in the art.

“Progroup” refers to a type of protecting group that, when used to maska functional group within an active 2,4-pyrimidinediamine drug to form apromoiety, converts the drug into a prodrug. Progroups are typicallyattached to the functional group of the drug via bonds that arecleavable under specified conditions of use. Thus, a progroup is thatportion of a promoiety that cleaves to release the functional groupunder the specified conditions of use. As a specific example, an amidepromoiety of the formula —NH—C(O)CH₃ includes the progroup —C(O)CH₃.

“Mammal” includes humans and domestic animals, such as cats, dogs,swine, cattle, sheep, goats, horses, rabbits, and the like. In someembodiments, the mammal is a human.

“Pharmaceutically acceptable carrier” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid (p-TSA),trifluoroacetic acid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, benethamine,benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine,triethanolamine, tromethamine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

A “pharmaceutical composition” refers to a formulation of a compoundprovided herein and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, for example,humans. Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof which, when administered to a mammal, such as a human, is sufficientto effect treatment, as defined below, of a disease or condition ofinterest in the mammal, (e.g., a human). The amount of a compound of theinvention which constitutes a “therapeutically effective amount” willvary depending on the compound, the disease or condition and itsseverity, and the age of the mammal to be treated, but can be determinedroutinely by one of ordinary skill in the art having regard to his ownknowledge and to this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, such as a human, havingthe disease or condition of interest, and includes at least one of thefollowing: (i) preventing the disease or condition from occurring in amammal, in particular, when such mammal is predisposed to the conditionbut has not yet been diagnosed as having it; (ii) inhibiting the diseaseor condition, by for example, arresting its development; (iii) relievingthe disease or condition, e.g., relieving the symptoms of disease orconditions, or causing regression of disease or condition; or (iv)stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds provided herein, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as HPLC using a chiralcolumn. When the compounds described herein contain olefinic doublebonds or other centres of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included. The compounds of the present invention do not include thosewhich are known in the art to be too unstable to synthesize and/orisolate.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

“Atropisomers” are stereoisomers resulting from hindered rotation aboutsingle bonds where the barrier to rotation is high enough to allow forthe isolation of the conformers (Eliel, E. L.; Wilen, S. H.Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994;Chapter 14). Atropisomerism is significant because it introduces anelement of chirality in the absence of stereogenic atoms. The inventionis meant to encompass atropisomers, of any said compounds and/orprodrugs provided herein.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are intended to be within the scope ofthe present invention.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

2,4-Pyrimidinediamine Compounds

In one aspect, provided herein is a compound according to Formula I:

or a pharmaceutically acceptable salt, a solvate, an N-oxide, or aprodrug thereof,

wherein:

Y¹ is O or S;

Z¹ is CH or N;

A is phenyl or a 6-membered heteroaryl;

R¹ is H;

R² and R³ are each, independently of one another, H, (C1-C6) alkyloptionally substituted with one or more of the same or different R¹¹groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R¹¹ groups, (C4-C11) cycloalkylalkyl optionallysubstituted with one or more of the same or different R¹¹ groups,(C5-C10) aryl optionally substituted with one or more of the same ordifferent R¹¹ groups, (C6-C16) arylalkyl optionally substituted with oneor more of the same or different R¹¹ groups, 2-6 membered heteroalkyloptionally substituted with one or more of the same or different R¹¹groups, 3-8 membered cycloheteroalkyl, optionally substituted with oneor more of the same or different R¹¹ groups, 4-11 memberedcycloheteroalkylalkyl, optionally substituted with one or more of thesame or different R¹¹ groups, 5-10 membered heteroaryl optionallysubstituted with one or more of the same or different R¹¹ groups or 6-16membered heteroarylalkyl optionally substituted with one or more of thesame or different R¹¹ groups;

R⁴ and R⁵ are each, independently of one another, H, (C1-C6) alkyl,(C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, (C1-C6) haloalkoxy, (C1-C6)aminoalkyl or (C1-C6) hydroxyalkyl; or, alternatively, R⁴ and R⁵, takentogether with the carbon atom to which they are bonded, form aspirocycloalkyl or a spirocycloheteroalkyl, or, alternatively, R⁴ andR⁵, taken together with the carbon atom to which they are bonded, form aC═O group;

R⁶ and R⁷ are each, independently of one another, H, (C1-C6) alkyl,(C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, (C1-C6) haloalkoxy, (C1-C6)aminoalkyl or (C1-C6) hydroxyalkyl; or, alternatively, R⁶ and R⁷, takentogether with the carbon atom to which they are bonded, form aspirocycloalkyl or a spirocycloheteroalkyl or, alternatively, R⁶ and R⁷,taken together with the carbon atom to which they are bonded, form a C═Ogroup;

R⁸ is H, halo, (C1-C6) alkyl optionally substituted with one or more ofthe same or different R¹¹ groups, (C1-C3) haloalkyloxy, —OR^(d),—SR^(d), —NR^(c)R^(c) (C1-C3) haloalkyl, —C(O)OR^(d), —CN, —NC, —OCN,—SCN, —NO or —NO₂;

two R⁹, taken together with the nitrogen atom to which they are bonded,form a 4- to 8-membered monocyclic cycloheteroalkyl, 6- to 10-memberedbridged bicyclic cycloheteroalkyl, or 6- to 12-membered bridgedtricyclic cycloheteroalkyl, wherein each may optionally be substitutedwith one or more of the same or different R¹¹ groups, and wherein thesubstituted or unsubstituted mono-, bi- or tricyclic cycloheteroalkylincludes at least two nitrogen atoms;

each R¹⁰ is independently R¹¹ or alternatively, two R¹⁰ on vicinalcarbons, taken together with the carbons to which they are bonded, forma ring fused to A, where the ring fused to A is a 5- to 8-memberedcycloalkyl, a 5- to 8-membered cycloheteroalkyl, 5- to 6-membered arylor a 5- to 6-membered heteroaryl, each optionally substituted with oneor more of the same or different R¹¹ groups;

each R¹¹ is independently H, R^(e), R^(b), R^(e) substituted with one ormore of the same or different R^(a) and/or R^(b), —OR^(e) substitutedwith one or more of the same or different R^(a) and/or R^(b), —SR^(e)substituted with one or more of the same or different R^(a) and/orR^(b), —C(O)R^(e) substituted with one or more of the same or differentR^(a) and/or R^(b), —N(R^(a))R^(e) where R^(e) is substituted with oneor more of the same or different R^(a) and/or R^(b), —S(O)₂R^(e)substituted with one or more of the same or different R^(a) and/orR^(b), —N(R^(a))—S(O)₂R^(e) where R^(e) is substituted with one or moreof the same or different R^(a) and/or R^(b), —B(OR^(a))₂,—B(N(R^(c))₂)₂, —(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(a))₂)_(m)—R^(b),—S—(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(b))₂)_(m)—R^(a),—N(R^(a))—(C(R^(a))₂)_(m)—R^(b), —O—(CH₂)_(m)—CH((CH₂)_(m)R^(b))R^(b),—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—O—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—N((C(R^(a))₂)_(m)R^(b))₂,—S—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—N(R^(a))—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—N(R^(a))—C(O)—(C(R^(a))₂)_(m)—C(R^(a))(R^(b))₂ or—N(R^(a))—(C(R^(a))₂)_(m)—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b);

each R^(a) is independently H, deuterium, (C1-6)alkyl, (C3-8)cycloalkyl,(C4-11)cycloalkylalkyl, (C6-10)aryl, (C7-16)arylalkyl, 2-6 memberedheteroalkyl, 3-10 membered heteroalicyclyl, 4-11 memberedheteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 memberedheteroarylalkyl;

each R^(b) is independently ═O, —OR^(a), —O—(C(R^(a))₂)_(m)—OR^(a),(C1-3)haloalkyloxy, —OCF₃, ═S, —SR^(a), ═NR^(a), ═NOR^(a), —N(R^(c))₂,halo, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a),—S(O)₂R^(a), —SO₃R^(a), —S(O)N(R^(c))₂, —S(O)₂N(R^(c))₂, —OS(O)R^(a),—OS(O)₂R^(a), —OSO₃R^(a), —OS(O)₂N(R^(c))₂, —C(O)R^(a), —CO₂R^(a),—C(O)N(R^(c))₂, —C(NR^(a))—N(R^(c))₂, —C(NOH)—R^(a), —C(NOH)—N(R^(c))₂,—OC(O)R^(a), —OC(O)OR^(a), —OC(O)N(R^(c))₂, —OC(NH)—N(R^(c))₂,—OC(NR^(a))—N(R^(c))₂, —N(R^(a))—S(O)₂H, —[N(R^(a))C(O)]_(n)R^(a),—[N(R^(a))C(O)]_(n)OR^(a), —[N(R^(a))C(O)]N(R^(c))₂ or—[N(R^(a))C(NR^(a))]_(n)—N(R^(c))₂;

each R^(c) is independently R^(a), or, alternatively, two R^(c) aretaken together with the nitrogen atom to which they are bonded to form a3 to 10-membered heteroalicyclyl or a 5-10 membered heteroaryl which mayoptionally include one or more of the same or different additionalheteroatoms and which is optionally substituted with one or more of thesame or different R^(a) and/or R^(d) groups;

each R^(d) is ═O, —OR^(a), —OCF₃, ═S, —SR^(a), ═NR^(a), ═NOR^(a),—N(R^(a))₂, halo, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃,—S(O)R^(a), —S(O₂)R^(a), —SO₃R^(a), —S(O)N(R^(a))₂, —S(O)₂N(R^(a))₂,—OS(O)R^(a), —OS(O)₂R^(a), —OSO₃R^(a), —OS(O)₂N(R^(a))₂, —C(O)R^(a),—CO₂R^(a), —C(O)N(R^(a))₂, —C(NR^(a))N(R^(a))₂, —C(NOH)R^(a),—C(NOH)N(R^(a))₂, —OCO₂R^(a), —OC(O)N(R^(a))₂, —OC(NR^(a))N(R^(a))₂,—[N(R^(a))C(O)]_(n)R^(a), —(C(R^(a))₂)_(n)—OR^(a), —N(R^(a))—S(O)₂R^(a),—C(O)—(C1-6)haloalkyl, —S(O)₂—(C1-6)haloalkyl, —OC(O)R^(a),—O(C(R^(a))₂)_(m)—OR^(a), —S(C(R^(a))₂)_(m)—OR^(a),—N(R^(a))—(C1-6)haloalkyl, —P(O)(OR^(a))₂,—N(R^(a))—(C(R^(a))₂)_(m)—OR^(a), —[N(R^(a))C(O)]_(n)OR^(a),—[N(R^(a))C(O)]_(n)N(R^(a))₂, —[N(R^(a))C(NR^(a))]_(n)N(R^(a))₂ or—N(R^(a))C(O)(C1-6)haloalkyl; two R^(d), taken together with the atom oratoms to which they are attached, combine to form a 3-10 memberedpartially or fully saturated mono or bicyclic ring, optionallycontaining one or more heteroatoms and optionally substituted with oneor more R^(a);

each R^(e) is independently (C1-6)alkyl, (C3-8)cycloalkyl,(C4-11)cycloalkylalkyl, (C6-10)aryl, (C7-16)arylalkyl, 2-6 memberedheteroalkyl, 3-10 membered heteroalicyclyl, 4-11 memberedheteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 memberedheteroarylalkyl;

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3;

provided:

the compound is not:

-   4-{3-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid methyl ester;-   N4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-[3-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;-   4-{3-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   1-(4-{3-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone;-   6-{5-Fluoro-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   6-{2-[3-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   4-{3-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   6-{5-Fluoro-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   6-{2-[3-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   4-{3-[5-Fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   N4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;-   N2-[3-Chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-N4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-pyrimidine-2,4-diamine;-   N4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;-   4-{4-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   1-(4-{4-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone;-   4-{4-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   4-{4-[5-Fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid ethyl ester;-   6-{5-Fluoro-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   6-{5-Fluoro-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   6-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;-   4-{4-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid methyl ester;-   4-{4-[5-Fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid methyl ester; or-   6-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one.

In some embodiments the compound of Formula I is further not:

-   N4-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine.

In some embodiments the compound of Formula I excludes compounds 141-171shown in Table 1, as well as

-   N4-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;    and-   4-{3-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic    acid methyl ester.

In some embodiments:

(i) when A is

and R^(c) is methyl, —C(O)OCH₃, —C(O)OCH₂CH₃ or —C(O)CH₃, the compoundof Formula I is not

(ii) when A is

wherein R^(c) is methyl, —C(O)OCH₃, —C(O)OCH₂CH₃ or —C(O)CH₃, thecompound of Formula I is not

and

(iii) when A is

wherein R^(c) is methyl and R¹⁰ is methyl or chloro, the compound ofFormula I is not

In addition to compounds described above, in some embodiments thecompound of Formula I is notN4-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine.

In some embodiments, the compound of Formula I does not includesimultaneously fluoro as R⁸ and a substituted or unsubstitutedpiperazinyl as —N(R⁹)₂.

In some embodiments, in the compound of Formula I, Y¹ is O. In someembodiments, in the compound of Formula I, Y¹ is S.

In some embodiments, in the compound of Formula I, Z¹ is CH. In someembodiments, in the compound of Formula I, Z¹ is N.

In some embodiments, in the compound of Formula I, A is phenyl. In someembodiments, in the compound of Formula I, A is a pyridyl.

In some embodiments, in the compound of Formula I, A is a 6-memberedheteroaryl having two nitrogen atoms.

In some embodiments, in the compound of Formula I, R² is H, (C1-C6)alkyl, (C3-C6) cycloalkyl or (C4-C6) cycloalkylalkyl. In more specificembodiments, R² is H.

In some embodiments R³, in the compound of Formula I is H, alkyl(including alkanyl, and alkynyl), haloalkyl, cycloalkyl,cycloalkylalkyl, arylalkyl optionally substituted with halo or alkoxy orheteroarylalkyl optionally substituted with halo or alkoxy.

In some embodiments, in the compound of Formula I, R⁴ and R⁵ are takentogether with the carbon atom to which they are bonded to form a C═Ogroup.

In some embodiments, in the compound of Formula I, R⁶ and R⁷, are each,independently of one another, H, halo or (C1-C6) alkyl, or,alternatively, R⁶ and R⁷ are taken together with the carbon atom towhich they are bonded to form an optionally substituted spirocycloalkylor an optionally substituted spirocycloheteroalkyl. In more specificembodiments, in the compound of Formula I, R⁶ and R⁷ are eachindependently H, halogen, methyl or ethyl. In some specific embodiments,in the compound of Formula I, R⁶ and R⁷ are simultaneously H. In somespecific embodiments, in the compound of Formula I, R⁶ and R⁷ aresimultaneously C1-C3 alkyl. In some specific embodiments, in thecompound of Formula I, R⁶ and R⁷ are taken together with the carbon atomto which they are bonded to form an unsubstituted spirocycloalkyl.

In some embodiments, in the compound of Formula I, R⁸ is H, (C1-C3)alkyl, (C1-C3) alkoxy, halogen, —CN, —NO₂, (C1-C3) haloalkyl,—C(O)OR^(d) or (C1-C3) haloalkyloxy. In more specific embodiments, inthe compound of Formula I, R⁸ is H, (C1-C3) alkyl, (C1-C3)perfluoroalkyl, fluoro, chloro or alkoxy. In even more specificembodiments, in the compound of Formula I, R⁸ is (C1-C3) perfluoroalkyl,fluoro or chloro.

In some embodiments, in the compound of Formula I, two R⁹ are takentogether with the nitrogen atom to which they are bonded form a 6- to10-membered bridged bicyclic or a 6- to 12-membered bridged tricyclicgroup, each optionally substituted with one or more of the same ordifferent R¹¹. In more specific embodiments, two R⁹ are taken togetherwith the nitrogen atom to which they are bonded form a 6- to 10-memberedbridged bicyclic group optionally substituted with one or more of thesame or different R¹¹. In some embodiments, the 6- to 10-memberedbridged bicyclic group includes a geometry which is [3.3.3], [3.3.2],[3.3.1], [3.2.2], [3.2.1], [2.2.2] or [2.2.1].

In some embodiments, the 6- to 10-membered bridged bicyclic groupincludes a nitrogen atom substituted with an R^(f) substituent, whereR^(f) is R^(a), —S(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d) or—C(O)NR^(c)R^(c). In a more specific embodiment, the 6- to 10-memberedbridged bicyclic group is

wherein R^(f) is R^(a), —S(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d) or—C(O)NR^(c)R^(c); and wherein each R^(g) is independently H, halogen or(C1-C6) alkyl.

In an even more specific embodiment the bridged bicyclic group is:

wherein R^(f) is R^(a), —S(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d) or—C(O)NR^(c)R^(c).

In more specific embodiments, R^(f) is H, (C1-C4) alkyl, (C4-C8)cycloalkylalkyl, —C(O)CH₃ or —SO₂CH₃, where R^(f) is a substituent at anitrogen on a 4- to 8-membered monocyclic cycloheteroalkyl, 6- to10-membered bridged bicyclic cycloheteroalkyl, or 6- to 12-memberedbridged tricyclic cycloheteroalkyl.

In some embodiments, in the compound of Formula I, the bridged bicyclicor bridged tricyclic group is

wherein R^(f) is R^(a), —S(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d) or—C(O)NR^(c)R^(c); and wherein each R⁹ is independently H, halogen or(C1-C6) alkyl. In more specific embodiments R^(f) is H, (C1-C4) alkyl,(C4-C8) cycloalkylalkyl, —C(O)CH₃ or —SO₂CH₃.

In some embodiments in the compound of Formula I, R¹⁰ is halogen,haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy orcycloalkylalkyloxy, or alternatively, two R¹⁰ on vicinal carbons, takentogether with the carbons to which they are bonded, form a ring fused toA, the ring fused to A being a 5- to 8-membered cycloalkyl, a 5- to8-membered cycloheteroalkyl, 5- to 6-membered aryl or a 5- to 6-memberedheteroaryl, each optionally substituted with one or more of the same ordifferent R¹¹ groups.

In a first specific embodiment, provided herein is a compound of FormulaII:

wherein,two R⁹ taken together with the nitrogen atom to which they are bondedform a 6- to 10-membered bridged bicyclic group optionally substitutedwith one or more of the same or different R¹¹, wherein the bridgedbicyclic group contains at least two annular nitrogen atoms;R¹⁰ is as defined above for compound I;R⁸ is H, (C1-C3) alkyl, (C1-C3) alkoxy, halogen, —CN, —NO₂, (C1-C3)haloalkyl, —C(O)OR^(d) or (C1-C3) haloalkyloxy;R² is H, (C1-C6) alkyl, (C3-C6) cycloalkyl or (C4-C6) cycloalkylalkyl;R³ is as defined above for Formula I;R⁶ and R⁷ are each, independently of one another, H, halo or (C1-C6)alkyl, or, alternatively, R⁶ and R⁷ are taken together with the carbonatom to which they are bonded to form an optionally substitutedspirocycloalkyl or an optionally substituted spirocycloheteroalkyl.

In a second embodiment, in accord with the first specific embodiment, R²is H.

In a third embodiment, in accord with the first specific embodiment orsecond embodiment thereof, the bridged bicyclic group is

wherein R^(f) is R^(a), —S(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d) or—C(O)NR^(c)R^(c); and wherein each R^(g) is independently H, halogen or(C1-C6) alkyl.

In a fourth embodiment, in accord with the third embodiment, R^(f) is H,(C1-C4) alkyl, (C4-C8) cycloalkylalkyl, —C(O)CH₃ or —SO₂CH₃; R¹⁰ ishalogen, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy orcycloalkylalkyloxy, or alternatively, two R¹⁰ on vicinal carbons, takentogether with the carbons to which they are bonded, form a ring fused toA, the ring fused to A being a 5- to 8-membered cycloalkyl, a 5- to8-membered cycloheteroalkyl, 5- to 6-membered aryl or a 5- to 6-memberedheteroaryl, each optionally substituted with one or more of the same ordifferent R¹¹ groups; R³ is as defined above for Formula I; R⁸ is H,(C1-C3) alkyl, (C1-C3) perfluoroalkyl, fluoro, chloro or alkoxy; and R⁶and R⁷ are each independently H, halogen, methyl or ethyl.

In a fifth embodiment, in accord with one of the first specificembodiment, the second, third or fourth embodiments, the compound isaccording to Formula III:

In a sixth embodiment, in accord with one of the first specificembodiment, the second, third or fourth embodiments, the compound isaccording to Formula IV:

In a seventh embodiment, in accord with one of the first specificembodiment, the second, third or fourth embodiments, the compound isaccording to Formula V:

In an eighth embodiment, in accord with one of the first specificembodiment, the second, third or fourth embodiments, the compound isaccording to Formula VI:

wherein the dashed line represents a bivalent linker, wherein thebivalent linker, together with the oxygens and annular carbon atoms towhich the oxygens are bonded, forms a 5- to 8-membered cycloheteroalkylring.

In a ninth embodiment, in accord with one of the first specificembodiment, the second, third or fourth embodiments, the compound isaccording to Formula VII:

In a tenth embodiment, in accord with one of the first specificembodiment, the second, third or fourth embodiments, the compound isaccording to one of the following formulae:

wherein the dashed line represents a bivalent linker, wherein thebivalent linker, together with the oxygens and annular carbon atoms towhich the oxygens are bonded, forms a 5- to 8-membered cycloheteroalkylring.

In an eleventh embodiment, in accord with compounds of Formula I,compounds of the invention have a structure according to Formula XIII:

whereintwo R⁹ taken together with the nitrogen atom to which they are bondedform a 6- to 10-membered bridged bicyclic group optionally substitutedwith one or more of the same or different R¹¹, wherein the bridgedbicyclic group contains at least two annular nitrogen atoms;R¹⁰ is as defined for compound I;R⁸ is H, (C1-C3) alkyl, (C1-C3) alkoxy, halogen, —CN, —NO₂, (C1-C3)haloalkyl, —C(O)OR^(d) or (C1-C3) haloalkyloxy;R² is H, (C1-C6) alkyl, (C3-C6) cycloalkyl or (C4-C6) cycloalkylalkyl;R³ is defined as for Formula I;R⁶ and R⁷ are each, independently of one another, H, halo or (C1-C6)alkyl, or alternatively, R⁶ and R⁷ are taken together with the carbonatom to which they are bonded to form an optionally substitutedspirocycloalkyl or an optionally substituted spirocycloheteroalkyl.

In a twelfth embodiment, is a compound of Formula XIII where R² is H.

In a thirteenth embodiment, is a compound having a structure as in theeleventh or twelfth embodiment, where the bridged bicyclic group is

where R^(f) is R^(a), —S(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d) or—C(O)NR^(c)R^(c); and each R^(g) is independently H, halogen or (C1-C6)alkyl.

In a fourteenth embodiment, is provided a compound with a structure asin the thirteenth embodiment, where R^(f) is H, (C1-C4) alkyl, (C4-C8)cycloalkylalkyl, —C(O)CH₃ or —SO₂CH₃; R¹⁰ is halogen, haloalkyl, alkyl,cycloalkyl, cycloalkylalkyl, alkoxy or cycloalkylalkyloxy, oralternatively, two R¹⁰ on vicinal carbons, taken together with thecarbons to which they are bonded, form a ring fused to A which is a 5-to 8-membered cycloalkyl, a 5- to 8-membered cycloheteroalkyl, 5- to6-membered aryl or a 5- to 6-membered heteroaryl, each optionallysubstituted with one or more of the same or different R¹¹ groups; R³ isdefined as for Formula I; R⁸ is H, (C1-C3) alkyl, (C1-C3)perfluoroalkyl, fluoro, chloro or alkoxy; and R⁶ and R⁷ are eachindependently H, halogen, methyl or ethyl.

In a fifteenth embodiment, is provided a compound according to any oneof the eleventh, twelfth, thirteenth and fourteenth embodiments having astructure according to Formula XIV:

In a sixteenth embodiment, is provided a compound according to any oneof the eleventh, twelfth, thirteenth and fourteenth embodiments having astructure according to Formula XV:

In a seventeenth embodiment, is provided a compound according to any oneof the eleventh, twelfth, thirteenth and fourteenth embodiments having astructure according to Formula XVI:

In an eighteenth embodiment, is provided a compound according to any oneof the eleventh, twelfth, thirteenth and fourteenth embodiments having astructure according to Formula XVII:

where the dashed line represents a bivalent linker, where the bivalentlinker, together with the oxygens and annular carbon atoms to which theoxygens are bonded, forms a 5-8 membered cycloheteroalkyl ring.

In a nineteenth embodiment, is provided a compound according to any oneof the eleventh, twelfth, thirteenth and fourteenth embodiments having astructure according to Formula XVIII:

In a twentieth embodiment, is provided a compound according to any oneof the eleventh, twelfth, thirteenth and fourteenth embodiments having astructure according to one of the following formulae:

where the dashed line represents a bivalent linker, wherein the bivalentlinker, together with the oxygens and annular carbon atoms to which theoxygens are bonded, forms a 5- to 8-membered cycloheteroalkyl ring.

In a twenty-first embodiment, the compound of Formula I has a structureof Formula XXIV:

where two R⁹ are taken together with the nitrogen atom to which they arebonded to form a 6- to 10-membered bridged bicyclic or a 6- to12-membered bridged tricyclic group, each optionally substituted withone or more of the same or different R¹¹.

In a twenty-second embodiment, the compound of Formula I has a structureof Formula XXV:

wherein two R⁹ are taken together with the nitrogen atom to which theyare bonded to form a 6- to 10-membered bridged bicyclic or a 6- to12-membered bridged tricyclic group, each optionally substituted withone or more of the same or different R¹¹.

In a twenty-third embodiment, the compound of Formula I is according toone of the following formulae:

whereinR⁹ and R¹⁰ are defined as for Formula I;R⁸ is H, (C1-C3) alkyl, (C1-C3) alkoxy, halo, —CN, —NO₂, (C1-C3)haloalkyl, —C(O)OR^(d) or (C1-C3) haloalkyloxy;R² is H, (C1-C6) alkyl, (C3-C6) cycloalkyl or (C4-C6) cycloalkylalkyl;R³ is as defined for Formula I;R⁶ and R⁷ are each, independently of one another, H, halo or (C1-C6)alkyl, or, alternatively, R⁶ and R⁷ are taken together with the carbonatom to which they are bonded to form an optionally substitutedspirocycloalkyl or an optionally substituted spirocycloheteroalkyl.

In a twenty-fourth embodiment, the compound is according to thetwenty-third embodiment where R² is H.

In a twenty-fifth embodiment, is provided a compound according to anyone of the twenty-third or twenty-fourth embodiment where the two R⁹groups are taken together with nitrogen to which the are bonded to form:

where R^(f) is R^(a), —S(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d) or—C(O)NR^(c)R^(c).

In a twenty-sixth embodiment, is provided a compound of the twenty-fifthembodiment where R^(f) is H, (C1-C4) alkyl, (C4-C8) cycloalkylalkyl,—C(O)CH₃ or —SO₂CH₃; R¹⁰ is halogen, haloalkyl, alkyl, cycloalkyl,cycloalkylalkyl, alkoxy or cycloalkylalkyloxy, or alternatively, two R¹⁰on vicinal carbons, taken together with the carbons to which they arebonded, form a ring fused to phenyl or pyridyl which is a 5- to8-membered cycloalkyl, a 5- to 8-membered cycloheteroalkyl, 5- to6-membered aryl or a 5- to 6-membered heteroaryl, each optionallysubstituted with one or more of the same or different R¹¹ groups; R³ isas defined for compound I; R⁸ is H, C1-C3 alkyl, C1-C3 perfluoroalkyl,fluoro, chloro or alkoxy; and R⁶ and R⁷ are each independently H,halogen, methyl or ethyl.

In a twenty-seventh embodiment, the compounds of embodiment twenty-six,have at least one R¹⁰ in an ortho position. The position is indicatedwith respect to N2 of the pyrimidinediamine system.

In a twenty-eighth embodiment, the compounds of embodiment twenty-sevenhave —N(R⁹)₂ in a meta position. The position is indicated with respectto N2 of the pyrimidinediamine system.

In a twenty-ninth embodiment, the compounds of embodiment twenty-eighthhave at least two R¹⁰ groups attached to vicinal carbons at the orthoand meta positions.

In a thirtieth embodiment, the compounds of embodiment twenty-nine havethe two R¹⁰ groups which together with the vicinal annular carbons towhich they are bonded form a ring fused to phenyl which is a 5- to8-membered cycloalkyl, a 5- to 8-membered cycloheteroalkyl, a 5- to6-membered aryl or a 5- to 6-membered heteroaryl, each optionallysubstituted with one or more of the same or different R¹¹ groups.

In a thirty-first embodiment, is a compound according to Formula I:

or a pharmaceutically acceptable salt, a solvate, an N-oxide, or aprodrug thereof,

wherein:

Y¹ is O or S;

Z¹ is CH or N;

A is phenyl or a 6-membered heteroaryl;

R¹ is H;

R² and R³ are each, independently of one another, H, (C1-C6) alkyloptionally substituted with one or more of the same or different R¹¹groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R¹¹ groups, (C4-C11) cycloalkylalkyl optionallysubstituted with one or more of the same or different R¹¹ groups,(C5-C10) aryl optionally substituted with one or more of the same ordifferent R¹¹ groups, (C6-C16) arylalkyl optionally substituted with oneor more of the same or different R¹¹ groups, 2-6 membered heteroalkyloptionally substituted with one or more of the same or different R¹¹groups, 3-8 membered cycloheteroalkyl, optionally substituted with oneor more of the same or different R¹¹ groups, 4-11 memberedcycloheteroalkylalkyl, optionally substituted with one or more of thesame or different R¹¹ groups, 5-10 membered heteroaryl optionallysubstituted with one or more of the same or different R¹¹ groups, and6-16 membered heteroarylalkyl optionally substituted with one or more ofthe same or different R¹¹ groups;

R⁴ and R⁵ are each, independently of one another, selected from thegroup consisting of H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy,halogen, (C1-C6) haloalkoxy, (C1-C6) aminoalkyl and (C1-C6)hydroxyalkyl, or, alternatively, R⁴ and R⁵, taken together with thecarbon atom to which they are bonded, form a spirocycloalkyl or aspirocycloheteroalkyl, or, alternatively, R⁴ and R⁵, taken together withthe carbon atom to which they are bonded, faun a C═O group;

R⁶ and R⁷ are each, independently of one another, selected from thegroup consisting of H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy,halogen, (C1-C6) haloalkoxy, (C1-C6) aminoalkyl and (C1-C6)hydroxyalkyl, or, alternatively, R⁶ and R⁷, taken together with thecarbon atom to which they are bonded, form a spirocycloalkyl or aspirocycloheteroalkyl or, alternatively, R⁶ and R⁷, taken together withthe carbon atom to which they are bonded, form a C═O group;

R⁸ is selected from the group consisting of H, halo, (C1-C6) alkyloptionally substituted with one or more of the same or different R¹¹groups, (C1-C3) haloalkyloxy, —OR^(d), —SR^(d), —NR^(c)R^(c), (C1-C3)haloalkyl, —C(O)OR^(d), —CN, —NC, —OCN, —SCN, —NO, and —NO₂;

two R⁹, taken together with the nitrogen atom to which they are bonded,form a 6- to 10-membered bridged bicyclic cycloheteroalkyl, which may beoptionally substituted with one or more of the same or different R¹¹groups, and wherein the substituted or unsubstituted bicycliccycloheteroalkyl includes at least two nitrogen atoms;

each R¹⁰ is independently R¹¹ or alternatively, two R¹⁰ on vicinalcarbons, taken together with the carbons to which they are bonded, forma ring fused to A selected from the group consisting of a 5- to8-membered cycloalkyl, a 5- to 8-membered cycloheteroalkyl, 5- to6-membered aryl and a 5- to 6-membered heteroaryl, each optionallysubstituted with one or more of the same or different R¹¹ groups;

each R¹¹ independently is R^(e), R^(b), R^(e) substituted with one ormore of the same or different R^(a) or R^(b), —OR^(a) substituted withone or more of the same or different R^(a) or R^(b), —B(OR^(a))₂,—B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b), —(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b), —O—CHR^(a)R^(b),O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))^(b)—R^(b),—C(O)NH—(CH₂)_(m)R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH(CH₂)_(m)—R^(b);

each R^(a) is independently selected from the group consisting ofhydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl,(C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10membered heteroaryl and 6-16 membered heteroarylalkyl;

each R^(b) is independently selected from the group consisting of ═O,OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d), ═NR^(d), ═NOR^(d),NR^(c)R^(c), halogen, haloalkyl, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂,—N₃, —S(O)R^(d), —S(O)₂R^(d), S(O)₂OR^(d), —S(O)NR^(c)R^(c);—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(c), —OS(O)₂OR^(d),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d),—OC(O)OR^(d), —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NHC(O)]_(n)OR^(d), [NHC(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c)and —[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);

each R^(c) is independently R^(a), or, alternatively, two R^(c) aretaken together with the nitrogen atom to which they are bonded to form a5 to 8-membered cycloheteroalkyl or heteroaryl, optionally including oneor more of the same or different additional annular heteroatoms andoptionally substituted with one or more of the same or different R^(a)or R^(b) groups;

each R^(d) is independently R^(a);

each R^(e) is independently selected from the group consisting of(C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10)aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 memberedcycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 memberedheteroaryl and 6-16 membered heteroarylalkyl;

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3.

Those of skill in the art will appreciate that the 2,4-pyrimidinediaminecompounds described herein may include functional groups that can bemasked with progroups to create prodrugs. Such prodrugs are usually, butneed not be, pharmacologically inactive until converted into theiractive drug form. For example, ester groups commonly undergoacid-catalyzed hydrolysis to yield the parent carboxylic acid whenexposed to the acidic conditions of the stomach, or base-catalyzedhydrolysis when exposed to the basic conditions of the intestine orblood. Thus, when administered to a subject orally,2,4-pyrimidinediamines that include ester moieties may be consideredprodrugs of their corresponding carboxylic acid, regardless of whetherthe ester form is pharmacologically active.

In the prodrugs described herein, any available functional moiety may bemasked with a progroup to yield a prodrug. Functional groups within the2,4-pyrimidinediamine compounds that may be masked with progroups forinclusion in a promoiety include, but are not limited to, amines(primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.Myriad progroups suitable for masking such functional groups to yieldpromoieties that are cleavable under the desired conditions of use areknown in the art. All of these progroups, alone or in combinations, maybe included in the prodrugs of the invention.

Additional exemplary embodiments of the compounds described herein areillustrated in the following Table 1, below. Table 1 listspyrimidinediamine compounds that have been prepared, as well as PLK1inhibition assay data for some of the compounds.

In some embodiments, the compounds have an IC₅₀ as against PLK1 of lessthan 10 μM, some less than 5 μM, some less than 1 μM, some less than 0.1μM, and some less than 0.01 μM with reference to a biochemical orcellular assay.

In some embodiments, compounds having an IC₅₀ of less than 10 μM in abiochemical in vitro PLK1 assay are compounds Nos. 3, 4-6, 15-21, 23-30,32-56, 95-97, 101, 107-111, 114-116, 120, 122, 125, 127-134, 157, 161,167-169, 173, 183, 188, 189, 191 and 196 presented in Table 1.

The results of the ability of the compounds described herein to inhibitPLK1 activity, when tested under conditions herein, are shown in Table1, where the activity is indicated by the following ranges: “A”represents compounds having an IC₅₀<0.5 μM; “B” represents compoundshaving an IC₅₀≧0.5 μM and <5 μM; “C” represents compounds having anIC₅₀≧5 μM and <10 μM; and “D” represents compounds having activity ≧10μM.

TABLE 1 PLK1 PLK1 IC₅₀ IC₅₀ (μM) (μM) bio- cel- chem- lu- ical lar as-as- # Structure Name say say 1

6-(2-(4-(4-(bicyclo[2.2.1]heptan-2- yl)piperazin-1-yl)phenylamino)-5-methylpyrimidin-4-ylamino)- 2,2,4-trimethyl- 2H-benzo[b][1,4]oxazin-3(4H)-one 2

6-(2-(4-(4-(bicyclo[2.2.1]heptan-2- yl)piperazin-1-yl)-3-fluorophenylamino)-5- methylpyrimidin-4-ylamino)- 2,2,4-trimethyl-2H-benzo[b][1,4]oxazin- 3(4H)-one 3

6-(5-fluoro-2-(3-methoxy-5-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one A 4

N4-(cyclobutylmethyl)- N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(3- (4-methylpiperazin-1-yl) phenyl)pyrimidine-2,4-diamine C 5

N4-(3,4-dihydro-2H-pyrido [3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(3-methoxy-5-(4- methylpiperazin-1-yl) phenyl)pyrimidine-2,4- diamine A6

6-(2-(3-(4-methylpiperazin- 1-yl)phenylamino)-5-(trifluoromethyl)pyrimidin- 4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one A 7

N4-(cyclohexylmethyl)- N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(3- (4-methylpiperazin-1- yl)phenyl)pyrimidine-2,4-diamine D 8

6-(5-fluoro-2-(3-isopropyl- 4-(5-methyl-2,5- diazabicyclo[2.2.1]heptan-2- yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b][1,4] oxazin-3(4H)-one D 9

N4-cyclohexyl-N4-(3,4- dihydro-2H-pyrido[3,2- b][1,4]oxazin-6-yl)-5-fluoro-N2-(3-(4- methylpiperazin-1-yl) phenyl)pyrimidine-2,4- diamine D10

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(3-isopropyl- 4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)phenyl)pyrimidine- 2,4-diamine D 11

methyl 4-(3,4-dihydro- 2H-pyrido[3,2- b][1,4]oxazin-6- ylamino)-2-(3-(4-methylpiperazin-1-yl) phenylamino)pyrimidine- 5-carboxylate D 12

4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-6- ylamino)-2-(3-(4-methylpiperazin-1- yl)phenylamino) pyrimidine-5-carboxylic acid D 13

6-(2-(3-(4- methylpiperazin-1- yl)phenylamino) pyrimidin-4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one D 14

6-(2-(3- (cyclobutylmethoxy)-5-(4- methylpiperazin-1- yl)phenylamino)-5-f!uoropyrimidin-4- ylamino)-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one D 15

N4-cyclobutyl-N4-(3,4- dihydro-2H-pyrido[3,2- b][1,4]oxazin-6-yl)-5-fluoro-N2-(3-(4- methylpiperazin-1-yl) phenyl)pyrimidine-2,4- diamineB 16

N2-(3- (cyclobutylmethoxy)-5-(4- methylpiperazin-1-yl)phenyl)-N4-(3,4-dihydro- 2H-pyrido[3,2-b] [1,4]oxazin-6-yl)-5-fluoropyrimidine- 2,4-diamine A 17

6-(5-fluoro-2-(3- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one A B 18

6-(5-fluoro-2- (3-(piperazin-1- yl)phenylamino)pyrimidin- 4-ylamino)-2H-benzo[b][1,4] oxazin-3(4H)-one A B 19

6-(5-fluoro-2-(3-(4- methylpiperazin-1- yl)phenylamino)pyrimidin-4-yiamino)-2H- pyrido[3,2-b] [1,4]oxazin-3(4H)-one hydrochloride A A 20

N4-(3,4-dihydro-2H-benzo[b] [1,4]oxazin-6-yl)- 5-fluoro-N2-(3-(4-methylpiperazin-1- yl)phenyl)pyrimidine- 2,4-diamine A B 21

N4-(3,4-dihydro-2H-pyrido [3,2-b][1,4]oxazin- 6-yl)-N2-(3-(4-methylpiperazin-1- yl)phenyl) pyrimidine-2,4-diamine A D 22

N4-(3,4-dihydro-2H-pyrido [3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(4-methyl-3-(4- methylpiperazin-1- yl)phenyl)pyrimidine-2.4- diamineD D 23

N4-(3,4-dihydro-2H-pyrido [3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(2-isopropoxy-5-(4- methylpiperazin-1- yl)phenyl)pyrimidine-2,4- diamineA B 24

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fIuoro-N2-(3-(4-methylpiperazin-1-yl)- 5-(trifluoromethyl) phenyl)pyrimidine-2,4-diamine A D 25

6-(5-fluoro-2- (3-isopropoxy-5-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one A A 26

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(3-isopropoxy-5-(4- methylpiperazin-1- yl)phenyl)pyrimidine-2,4- diamineA A 27

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(2-isopropyl-5-(4- methylpiperazin-1- yl)phenyl)pyrimidine-2,4- diamineA B 28

5-fluoro-N2-(3-methyl- 4-(5-(methylsulfonyl)- 2.5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)- N4-(4-propyl-3,4- dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl) pyrimidine-2,4-diamine B B 29

6-(5-fluoro-2-(3-(4- methylpiperazin-1-yl)-5- (trifluoromethyl)phenylamino)pyrimidin-4- ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one A D 30

6-(5-fluoro-2-(2- isopropoxy-5-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one A A 31

6-(5-fluoro-2-(3-methyl- 4-(5-(methylsulfonyl)- 2,5-diazabicyclo[2.2.1]heptan-2- yl)phenylamino)pyrimidin- 4-ylamino)-4-propyl-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one D B 32

6-(5-methyl-2-(3-methyl-4- (5-(methylsulfonyl)- 2,5-diazabicyclo[2.2.1]heptan-2- yl)phenylamino)pyrimidin- 4-ylamino)-4-propyl-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one B B 33

5-methyl-N2-(3-methyl- 4-(5-(methylsulfonyl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)- N4-(4-propyl-3,4- dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl) pyrimidine-2,4-diamine A B 34

N2-(2-cyclopropyl-5- (4-methylpiperazin-1- yl)phenyl)-N4-(3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazin-6-yl)- 5-fluoropyrimidine-2,4-diamine A A 35

6-(2-(4-(5-acetyl-2,5- diazabicyclo[2.2.1] heptan-2-yl)-3-methylphenylamino)- 5-fluoropyrimidin-4- ylamino)-4-propyl-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one A B 36

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(4-methyl-3-(5-methyl-2,5- diazabicyclo [2.2.1]heptan-2-yl)phenyl)pyrimidine- 2,4-diamine A B 37

1-(5-(4-(5-fluoro-4-(4- propyl-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-6-ylamino)pyrimidin- 2-ylamino)-2- methylphenyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)ethanone B B 38

6-(2-(4-(5-acetyl-2,5- diazabicyclo[2.2.1] heptan-2-yl)-3-methylphenylamino)- 5-methylpyrimidin-4- ylamino)-4-propyl-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one A B 39

1-(5-(2-methyl-4-(5- methyl-4-(4-propyl-3,4- dihydro-2H-pyrido[3,2-b][1,4]oxazin-6- ylamino)pyrimidin-2- ylamino)phenyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)ethanone B B 40

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-methyl-N2-(3-(4-methylpiperazin-1- yl)phenyl)pyrimidine- 2,4-diamine A B 41

6-(5-fluoro-2- (3-(5-methyl-2,5- diazabicyclo [2.2.1]heptan-2-yl)phenylamino) pyrimidin-4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one A A 42

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(3-(5-methyl-2,5- diazabicyclo [2.2.1]heptan-2- yl)phenyl)pyrimidine-2,4-diamine A A 43

6-(5-fluoro-2- (2-isopropyl-5-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one A A 44

6-(5-fluoro-2- (3-isopropyl-5-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one A D 45

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-N2-(2-ethoxy-5-(4-methyipiperazin-1- yl)phenyl)-5- fluoropyrimidine- 2,4-diamine A A 46

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(3-isopropyl-5-(4- methylpiperazin-1- yl)phenyl)pyrimidine-2,4-diamine A B 47

6-(2-(3-tert-butoxy- 5-(4-methylpiperazin-1- yl)phenylamino)-5-fluoropyrimidin-4-ylamino)- 2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one A A48

N2-(3-cyclopropyl-5- (4-methylpiperazin-1- yl)phenyl)-N4-(3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazin-6-yl)- 5-fluoropyrimidine-2,4-diamine A A 49

6-(2-(2-ethoxy-5- (4-methylpiperazin-1- yl)phenylamino)-5-fluoropyrimidin-4-ylamino)- 2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one A A50

6-(2-(3-cyclopropyl-5- (4-methylpiperazin-1- yl)phenylamino)-5-fluoropyrimidin-4-ylamino)- 2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one A A51

6-(5-methyl-2-(3- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2H- pyrido[3,2-b] [1,4]oxazin-3(4H)-one A B 52

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-methoxy-N2-(3-(4-methylpiperazin-1- yl)phenyl)pyrimidine- 2,4-diamine A B 53

N4-(cyclopropylmethyl)- N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(3- (4-methylpiperazin-1- yl)phenyl)pyrimidine-2,4-diamine B D 54

N4-cyclopentyl- N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(3- (4-methylpiperazin-1- yl)phenyl)pyrimidine-2,4-diamine C D 55

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-N2-(3-(4-methylpiperazin-1- yl)phenyl)-5- (trifluoromethyl)pyrimidine-2,4-diamine A A 56

6-(5-methoxy-2-(3- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2H- pyrido[3,2-b] [1,4]oxazin-3(4H)-one A D 57

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(4-(5-methyl-2,5- diazabicyclo[2.2.1] heptan-2-yl)-3-(trifluoromethyl)phenyl) pyrimidine-2,4-diamine D 58

6-(5-chloro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-propyl- 2H-benzo[b][1,4]oxazin- 3(4H)-one formate 59

6-(5-chloro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-(3- fluoropropyl)-2H-benzo[b] [1,4]oxazin-3(4H)- oneformate 60

6-(5-chloro-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-4- (3-fluoropropyl)-2H- benzo[b][1,4]oxazin-3(4H)-one formate 61

4-(2-fluoroethyl)-6- (5-methyl-2-(4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-benzo[b] [1,4]oxazin-3(4H)-oneformate 62

6-(5-chloro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-(2- fluoroethyl)-2H-benzo[b] [1,4]oxazin-3(4H)- one formate63

6-(5-chloro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylammo)-4-(2- fluoroethyl)-2,2- dimethyl-2H- benzo[b][1,4]oxazin-3(4H)-one formate 64

6-(5-fluoro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-propyl- 2H-benzo[b][1,4]oxazin- 3(4H)-one formate 65

6-(5-fIuoro-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-4- propyl-2H-benzo[b] [1,4]oxazin-3(4H)-one formate66

6-(5-methyl-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-propyl- 2H-benzo[b][1,4]oxazin- 3(4H)-one formate 67

6-(5-methyl-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-4- propyl-2H-benzo[b] [1,4]oxazin-3(4H)-one formate68

2,2-dimethyl-6- (5-methyl-2-(6-(4- methylpiperazin- 1-yl)pyridin-3-ylamino)pyrimidin-4- ylamino)-4-propyl-2H- benzo[b][1,4]oxazin-3(4H)-one formate 69

4-(3-fluoropropyl)-6- (5-methyl-2-(6-(4- methylpiperazin-1-yl)pyridin-3- ylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin-3(4H)-one formate 70

6-(5-chloro-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-2,2- dimethyl-4-propyl-2H- benzo[b][1,4]oxazin-3(4H)-one formate 71

6-(5-chloro-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-4- propyl-2H-benzo[b] [1,4]oxazin-3(4H)-one formate72

4-(2-fluoroethyl)-6- (5-methyl-2-(6-(4- methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one formate73

6-(5-chloro-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-4- (2-fluoroethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one formate 74

6-(5-chloro-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-4- (2-fluoroethyl)- 2,2-dimethyl-2H-benzo[b][1,4]oxazin- 3(4H)-one formate 75

6-(5-fluoro-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one formate 76

6-(5-methyl-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one formate 77

6-(5-methyl-2-(6- (piperazin-1-yl)pyridin-3- ylamino)pyrimidin-4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one formate 78

tert-butyl 4-(5-(5-methyl- 4-(3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-ylamino)pyrimidin- 2-ylamino)pyridin- 2-yl)piperazine-1- carboxylateformate 79

6-(2-(6-(4-ethylpiperazin- 1-yl)pyridin-3- ylamino)-5-methylpyrimidin-4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one formate 80

6-(2-(6-(4-isopropylpiperazin- 1-yl)pyridin-3-ylamino)-5-methylpyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin-3(4H)-one formate 81

6-(2-(6-(4-(cyclopropylmethyl) piperazin-1- yl)pyridin-3-ylamino)-5-methylpyrimidin-4- ylamino)-2H-benzo[b] [1,4]oxazin-3(4H)-one formate82

6-(2-(6-(4-benzylpiperazin- 1-yl)pyridin-3- ylamino)-5-methylpyrimidin-4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one formate 83

6-(5-methyl-2-(6- (4-methylpiperazin-1- yl)pyridazin-3-ylamino)pyrimidin-4-ylamino)- 2H-benzo[b][1,4]oxazin- 3(4H)-one formate 84

6-(5-methyl-2-(6-(4- (methylsulfonyl)piperazin- 1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)- 2H-benzo[b][1,4]oxazin- 3(4H)-one formate 85

2,2,4-trimethyl-6-(5-methyl- 2-(3-methyl-4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-benzo[b] [1,4]oxazin-3(4H)-one86

6-(5-ethyl-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2,2,4- trimethyl-2H-benzo[b] [1,4]oxazin-3(4H)-one87

4-methyl-6-(5-methyl-2- (4-(4-methylpiperazin- 1-yl)phenylamino)pyrimidin-4-ylamino)-2H- pyrido[3,2-b] [1,4]oxazin-3(4H)-one 88

2,2-dimethyl-6- (5-methyl-2-(4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one D 89

6-(5-methyl-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-propyl- 2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one 90

2,2,4-trimethyl- 6-(5-methyl-2-(4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one 91

6-(2-(4-(4-ethylpiperazin- 1-yl)phenylamino)-5- methylpyrimidin-4-ylamino)-4-methyl-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-one D 92

6-(2-(4-(4-ethylpiperazin- 1-yl)phenylamino)-5- methylpyrimidin-4-ylamino)-2,2-dimethyl-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-one D 93

6-(2-(4-(4-ethylpiperazin- 1-yl)phenylamino)-5- methylpyrimidin-4-ylamino)-4-propyl-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-one 94

6-(2-(4-(4-ethylpiperazin-1- yl)phenylamino)-5- methylpyrimidm-4-ylamino)-2,2,4-trimethyl- 2H-pyrido[3,2-b][1,4]oxazin- 3(4H)-one D 95

4-methyl-6-(5-methyl- 2-(3-methyl-4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one B D 96

2,2-dimethyl-6-(5-methyl- 2-(3-methyl-4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one C D 97

6-(5-methyl-2-(3-methyl- 4-(4-methylpiperazin- 1-yl)phenylamino)pyrimidin-4-ylamino)-4- propyl-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one AB 98

2,2,4-trimethyl-6-(5- methyl-2-(3-methyl-4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one D 99

4-methyl-6-(5-methyl-2- (6-(4-methylpiperazin- 1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)- 2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one 100

2,2-dimethyl-6- (5-methyl-2-(6-(4- methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4- ylamino)-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one 101

4-ethyl-6-(5-methyl-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pynmidin-4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-one A B 102

2,2,4-trimethyl-6- (5-methyl-2-(6-(4- methylpiperazin- 1-yl)pyridin-3-ylamino)pyrimidin-4- ylamino)-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one 103

2,2,4-trimethyl-6-(5- methyl-2-(3-methyl-4-(5- methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)phenylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin-3(4H)-one 104

2,2-dimethyl-6-(5- methyl-2-(3-methyl-4-(5- methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)phenylamino)pyrimidin- 4-ylamino)-2H-benzo[b][1,4]oxazin- 3(4H)-one 105

2,2-dimethyl-6-(5-methyl- 2-(3-methyl-4-(5- methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b][1,4]oxazin- 3(4H)-one 106

2,2,4-trimethyl-6-(5-methyl- 2-(3-methyl-4-(5- methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b][1,4]oxazin- 3(4H)-one 107

6-(5-methyl-2-(3-methyl- 4-(5-methyl-2,5- diazabicyclo[2.2.1] heptan-2-yl)phenylamino)pyrimidin- 4-ylamino)-4-propyl-2H-pyrido[3,2-b][1,4]oxazin- 3(4H)-one A B 108

4-(cyclopropylmethyl)-6- (5-fluoro-2-(3-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one A B 109

4-(cyclobutylmethyl)-6- (5-fluoro-2-(3-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one A B 110

4-(cyclohexylmethyl)-6- (5-fluoro-2-(3-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one C D 111

4-(cyclopropylmethyl)-6- (5-fluoro-2-(3-methyl- 4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one B 112

4-(cyclobutylmethyl)-6- (5-fluoro-2-(3-methyl- 4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one D D 113

4-(cyclohexylmethyl)-6- (5-fluoro-2-(3-methyl- 4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one D D 114

4-(cyclopropylmethyl)-6- (5-methyl-2-(3- methyl-4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one B D 115

4-(cyclobutylmethyl)-6- (5-methyl-2-(3-methyl- 4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one B D 116

4-cyclopentyl-6- (5-methyl-2-(3-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one B D 117

4-cyclopentyl-6-(5-methyl- 2-(3-methyl-4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one D D 118

4-benzyl-6-(5-fluoro- 2-(3-methyl-4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one D B 119

4-(cyclohexylmethyl)-6- (5-methyl-2-(3-methyl- 4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one D D 120

4-benzyl-6-(5-fluoro-2- (3-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one B B 121

4-benzyl-6-(5-methyl-2- (3-methyl-4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one D B 122

4-benzyl-6-(5-methyl-2- (3-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one A B 123

6-(5-fluoro-2-(3-(4- methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-(4- methoxybenzyl)-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-oneD D 124

6-(5-fluoro-2-(3-methyl-4- (4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-4-(4- methoxybenzyl)-2H-pyrido[3,2-b][1,4]oxazin- 3(4H)-one D D 125

4-(4-methoxybenzyl)-6- (5-methyl-2-(3-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one C D 126

4-(4-methoxybenzyl)-6- (5-methyl-2-(3-methyl- 4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one D B 127

6-(5-methyl-2-(3- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-(prop- 2-ynyl)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one A A128

6-(5-fluoro-2-(3- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-(prop- 2-ynyl)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one A B129

4-(cyclopropylmethyl)- 6-(5-methyl-2-(3-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one A B 130

4-(cyclobutylmethyl)-6- (5-methyl-2-(3-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one A B 131

4-cyclopentyl-6- (5-fluoro-2-(3-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one B D 132

6-(5-fluoro-2-(3- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-(4- fluorobenzyl)-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-one CB 133

4-(4-fluorobenzyl)- 6-(5-methyl-2-(3-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one A B 134

6-(5-fluoro-2-(3- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4- (pentan-3-yl)-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one A A 135

6-(5-fluoro-2-(4- (4-methylpiperazin-1-yl)-3- (trifIuoromethyl)phenylamino)pyrimidin-4- ylamino)-4-propyl- 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one D D 136

6-(5-methyl-2-(4- (4-methylpiperazin-1-yl)-3- (trifluoromethyl)phenylamino)pyrimidin-4- ylamino)-4-propyl- 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one D D 137

6-(5-fluoro-2-(4-(4- (methylsulfonyl)piperazin- 1-yl)-3-(trifluoromethyl) phenylamino)pyrimidin-4- ylamino)-4-propyl-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one D D 138

6-(5-fluoro-2- (4-(piperazin-1yl)-3- (trifluoromethyl)phenylamino)pyrimidin-4- ylamino)-4- propyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one D D 139

2,2-difluoro-6-(5- methyl-2-(3-methyl-4-(5- methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)phenylamino) pyrimidin-4-ylamino)-4-(pyridin-2-ylmethyl)- 2H-benzo[b][1,4]oxazin- 3(4H)-one D C 140

2,2-difluoro-6-(5- methyl-2-(3-methyl-4-(5- methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)phenylamino) pyrimidin-4-ylamino)-2H-benzo[b][1,4]oxazin-3(4H)-one 141

2,2-difluoro-4-methyl- 6-(5-methyl-2-(3-methyl- 4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)phenylamino) pyrimidin-4-ylamino)-2H-benzo[b][1,4] oxazin-3(4H)-one 142

2,2-difluoro-6- (2-(4-(5-isobutyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)-3- methylphenylamino)- 5-methylpyrimidin-4-ylamino)-4-methyl- 2H-benzo[b][1,4]oxazin- 3(4H)-one 143

6-(5-methyl-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-one 144

2,2,4-trimethyl-6-(5- methyl-2-(5-methyl-6-(5- methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyridin-3-ylamino) pyrimidin-4-ylamino)-2H-pyrido[3,2-b][1,4]oxazin- 3(4H)-one 145

2,2-dimethyl-6-(5-methyl- 2-(5-methyl-6-(4- methylpiperazin-1-yl)pyridin-3- ylamino)pyrimidin-4- ylamino)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one 146

2,2-dimethyl-6-(5- methyl-2-(5-methyl-6-(5- methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyridin-3-ylamino) pyrimidin-4-ylamino)-2H-pyrido[3,2-b][1,4]oxazin- 3(4H)-one 147

6-(5-methyl-2-(5- methyl-6-(5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-3- ylamino)pyrimidin-4- ylamino)-4-propyl-2H-pyrido[3,2-b][1,4] oxazin-3(4H)-one 148

6-(2-(4-(4-acetylpiperazin- 1-yl)phenylamino)- 5-fluoropyrimidin-4-ylamino)-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one 149

methyl 4-(4-(5-fluoro- 4-(3-oxo-3,4-dihydro- 2H-pyrido[3,2-b][1,4]oxazin-6- ylamino)pyrimidin-2- ylamino)phenyl)piperazine- 1-carboxylate150

methyl 4-(4-(4-(2,2- dimethyl-3-oxo-3,4- dihydro-2H-pyrido[3,2-b][1,4]oxazin-6- ylamino)-5- fluoropyrimidin-2-ylamino)phenyl)piperazine- 1-carboxylate 151

6-(2-(4-(4-acetylpiperazin- 1-yl)phenylamino)- 5-fluoropyrimidin-4-ylamino)-2,2-dimethyl-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-one 152

6-(5-fluoro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-one 153

6-(5-fluoro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2,2- dimethyl-2H-pyrido [3,2-b][1,4]oxazin-3(4H)-one 154

ethyl 4-(3-(5-fIuoro-4- (3-oxo-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-6-ylamino)pyrimidin- 2-ylamino)phenyl) piperazine-1-carboxylate 155

6-(2-(3-(4-acetylpiperazin- 1-yl)phenylamino)- 5-fluoropyrimidin-4-ylamino)-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one 156

ethyl 4-(4-(5-fluoro-4- (3-oxo-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-6-ylamino)pyrimidin- 2-ylamino)phenyl)piperazine- 1-carboxylate 157

6-(5-fluoro-2-(3- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-one A A 158

ethyl 4-(3-(4-(2,2-dimethyl- 3-oxo-3,4-dihydro- 2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5- fluoropyrimidin-2- ylamino)phenyl)piperazine-1-carboxylate 159

6-(2-(3-(4-acetylpiperazin- 1-yl)phenylamino)- 5-fluoropyrimidin-4-ylamino)-2,2-dimethyl-2H- pyrido[3,2-b][1,4]oxazin- 3(4H)-one 160

ethyl 4-(4-(4-(2,2-dimethyl- 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin- 6-ylamino)-5- fluoropyrimidin-2-ylamino)phenyl)piperazine- 1-carboxylate 161

6-(5-fluoro-2-(3- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2,2- dimethyl-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)- one A B 162

1-(4-(4-(4-(3,4-dihydro- 2H-pyrido[3,2- b]oxazin-6-ylamino)-5-fluoropyrimidin-2- ylamino)phenyl) piperazin-1-yl)ethanone 163

ethyl 4-(4-(4-(3,4- dihydro-2H-pyrido[3,2- b][1,4]oxazin-6-ylamino)-5-fluoropyrimidin-2- ylamino)phenyl) piperazine-1-carboxylate D 164

1-(4-(3-(4-(3,4- dihydro-2H-pyrido[3,2- b][1,4]oxazin-6-ylamino)-5-fluoropyrimidin-2- ylamino)phenyl)piperazin- 1-yl)ethanone D 165

ethyl 4-(3-(4-(3,4- dihydro-2H-pyrido[3,2- b][1,4]oxazin-6-ylamino)-5-fluoropyrimidin-2- ylamino)phenyl)piperazine- 1-carboxylate D 166

N4-(3(4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(4-(4-methylpiperazin-1- yl)phenyl)pyrimidine- 2,4-diamine D 167

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(3-(4-methylpiperazin-1- yl)phenyl)pyrimidine- 2,4-diamine A A 168

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(3-(4-methylpiperazin-1- yl)phenyl)pyrimidine-2,4- diamine p-toluenesulfonic acid salt A A 169

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(3-(4-methylpiperazin-1- yl)phenyl)pyrimidine- 2,4-diamine hydrochloridesalt A A 170

N2-(3-chloro-4- (4-methylpiperazin-1- yl)phenyl)-N4-(3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazin-6-yl)- 5-fluoropyrimidine-2,4-diamine 171

N4-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin- 6-yl)-5-fluoro-N2-(3-methyl-4-(4- methylpiperazin-1- yl)phenyl)pyrimidine-2,4- diamine172

6-(5-chloro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2,2- dimethyl-4-propyl- 2H-benzo[b][1,4]oxazin- 3(4H)-one 173

6-(5-chloro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-ethyl- 2H-benzo[b][1,4]oxazin- 3(4H)-one B B 174

6-(5-chloro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-(prop- 2-ynyl)-2H-benzo[b] [1,4]thiazin-3(4H)-one 175

2,2-dimethyl-6- (5-methyl-2-(4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-4-propyl-2H- benzo[b][1,4]oxazin-3(4H)-one 176

4-ethyl-2,2-dimethyl- 6-(5-methyl-2-(4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-benzo[b] [1,4]oxazin-3(4H)-one177

6-(5-chloro-2-(4- (4-methyipiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-ethyl- 2,2-dimethyl-2H- benzo[b][1,4]oxazin- 3(4H)-one 178

6-(5-chloro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2,2,4- trirnethyl-2H-benzo[b] [1,4]oxazin-3(4H)-one 179

6-(2-(4-(4-ethylpiperazin- 1-yl)phenylamino)-5- methylpyrimidin-4-ylamino)-4-methyl-2H- benzo[b][1,4]thiazin- 3(4H)-one 180

6-(5-chloro-2-(4- (4-ethylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4- methyl-2H-benzo[b] [1,4]thiazin-3(4H)-one 181

6-(2-(4-(4-ethylpiperazin- 1-yl)phenylamino)-5- methylpyrimidin-4-ylamino)-4-methyl-2H- benzo[b][1,4]oxazin- 3(4H)-one 182

6-(5-chloro-2-(4- (4-ethylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4- methyl-2H-benzo[b] [1,4]oxazin-3(4H)-one 183

6-(5-chloro-2-(4- (4-ethylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-ethyl- 2H-benzo[b][1,4]oxazin- 3(4H)-one B B 184

6-(2-(4-(4-ethylpiperazin- 1-yl)phenylamino)-5- methylpyrimidin-4-ylamino)-2,2,4-trimethyl- 2H-benzo[b][1,4]oxazin- 3(4H)-one 185

6-(5-chloro-2-(4- (4-ethylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2,2,4- trimethyl-2H-benzo[b] [1,4]oxazin-3(4H)-one 186

4-ethyl-6-(2-(4- (4-ethylpiperazin-1- yl)phenylamino)-5-methylpyrimidin-4- ylamino)-2,2- dimethyl-2H- benzo[b][1,4]oxazin-3(4H)-one 187

6-(5-chloro-2-(4- (4-ethylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-4-ethyl- 2,2-dimethyl-2H-benzo[b] [1,4]oxazin-3(4H)- one 188

4-(3-fluoropropyl)- 6-(5-methyl-2-(4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-benzo[b] [1,4]oxazin-3(4H)-one BB 189

4-ethyl-6-(5-methyl-2- (4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-oneB B 190

4-methyl-6-(5-methyl- 2-(3-methyl-4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-benzo[b] [1,4]oxazin-3(4H)-one 191

4-ethyl-6-(5-methyl- 2-(3-methyl-4-(4- methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H-benzo[b] [1,4]oxazin-3(4H)-one C D192

6-(5-chloro-2-(3-methyl- 4-(4-methylpiperazin- 1-yl)phenylamino)pyrimidin-4-ylamino)-4- methyl-2H-benzo[b] [1,4]oxazin-3(4H)-one 193

4-ethyl-2,2-dimethyl-6- (5-methyl-2-(3-methyl- 4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one194

6-(5-chloro-2-(3-methyl- 4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2,2,4- trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one 195

4-methyl-6- (5-methyl-2-(4-(4- (methylsulfonyl)piperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one196

4-ethyl-6-(5- methyl-2-(4-(4- (methylsulfonyl) piperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-oneB C 197

6-(5-chloro-2-(4-(4- (methylsulfonyl)piperazin- 1-yl)phenylamino)pyrimidin-4-ylamino)-4- methyl-2H-benzo[b] [1,4]oxazin-3(4H)-one D B 198

2,2,4-trimethyl-6- (5-methyl-2-(4-(4- (methylsulfonyl) piperazin-1-yl)phenylamino) pyrimidin-4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one199

4-ethyl-2,2-dimethyl- 6-(5-methyl-2-(4-(4- (methylsulfonyl) piperazin-1-yl)phenylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one200

6-(5-chloro-2-(4-(4- (methylsulfonyl)piperazin- 1-yl)phenylamino)pyrimidin-4-ylamino)-2,2,4- trimethyl-2H-benzo[b] [1,4]oxazin-3(4H)-one201

4-methyl-6-(5-methyl- 2-(6-(4-methylpiperazin- 1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)- 2H-benzo[b][1,4]oxazin- 3(4H)-one 202

2,2,4-trimethyl-6- (5-methyl-2-(6-(4- methylpiperazin- 1-yl)pyridin-3-ylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one D 203

6-(5-chloro-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)- 2,2,4-trimethyl-2H- benzo[b][1,4]oxazin-3(4H)- one204

6-(5-chloro-2-(4- (4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)-2,2- diethyl-4-methyl- 2H-benzo[b][1,4]oxazin- 3(4H)-one 205

6-(5-chloro-2-(6- (4-methylpiperazin-1- yl)pyridin-3-ylamino)pyrimidin-4-ylamino)-2,2- diethyl-4-methyl-2H- benzo[b][1,4]oxazin-3(4H)-one 206

4-methyl-6-(5-methyl- 2-(4-(4-methylpiperazin- 1-yl)phenylamino)pyrimidin-4- ylamino)spiro[benzo[b] [1,4]oxazine-2,1′-cyclopropan]-3(4H)-one 207

4-methyl-6-(5-methyl- 2-(6-(4-methylpiperazin- 1-yl)pyridin-3-ylamino)pyrimidin-4- ylamino)spiro[benzo[b] [1,4]oxazine-2,1′-cyclopropan]-3(4H)-one 208

4-methyl-6-(5-methyl- 2-(5-methyl-6-(4- methylpiperazin- 1-yl)pyridin-3-ylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one 209

2,2,4-trimethyl-6-(5- methyl-2-(5-methyl-6-(4- methylpiperazin-1-yl)pyridin-3- ylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin-3(4H)-one 210

6-(5-chloro-2-(5-methyl- 6-(4-methylpiperazin- 1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)- 2,2,4-trimethyl-2H- benzo[b][1,4]oxazin- 3(4H)-one211

2,2-dimethyl-6-(5-methyl- 2-(5-methyl-6-(4- methylpiperazin-1-yl)pyridin-3- ylamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin-3(4H)-one 212

2,2-dimethyl-6- (5-methyl-2-(6-(4- methylpiperazin- 1-yl)pyridin-3-yiamino)pyrimidin- 4-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one

One of ordinary skill in the art will appreciate that many of thecompounds and prodrugs described herein, as well as the various compoundspecies specifically described and/or illustrated herein, may exhibitthe phenomena of tautomerism, conformational isomerism, geometricisomerism and/or optical isomerism. For example, the compounds andprodrugs may include one or more chiral centers and/or double bonds andas a consequence may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers and diastereomers and mixturesthereof, such as racemic mixtures. As another example, the compounds andprodrugs may exist in several tautomeric forms, including the enol form,the keto form and mixtures thereof. As the various compound names,formulae and compound drawings within the specification and claims canrepresent only one of the possible tautomeric, conformational isomeric,optical isomeric or geometric isomeric forms, it should be understoodthat the invention encompasses any tautomeric, conformational isomeric,optical isomeric and/or geometric isomeric forms of the compounds orprodrugs having one or more of the utilities described herein, as wellas mixtures of these various different isomeric forms. In cases oflimited rotation around the 2,4-pyrimidinediamine core structure,atropisomers are also possible and are also specifically included in thecompounds and/or prodrugs of the invention.

Depending upon the nature of the various substituents, the2,4-pyrimidinediamine compounds and prodrugs may be in the form ofsalts. Such salts include salts suitable for pharmaceutical uses(“pharmaceutically-acceptable salts”), salts suitable for veterinaryuses, etc. Such salts may be derived from acids or bases, as iswell-known in the art.

In some embodiments, the salt is a pharmaceutically acceptable salt.Generally, pharmaceutically acceptable salts are those salts that retainsubstantially one or more of the desired pharmacological activities ofthe parent compound and which are suitable for administration to humans.Pharmaceutically acceptable salts include acid addition salts formedwith inorganic acids or organic acids. Inorganic acids suitable forforming pharmaceutically acceptable acid addition salts include, by wayof example and not limitation, hydrohalide acids (e.g., hydrochloricacid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids suitable for formingpharmaceutically acceptable acid addition salts include, by way ofexample and not limitation, acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, palmiticacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, alkylsulfonic acids (egg, methanesulfonic acid,ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonicacid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, etc.),4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like.

Pharmaceutically acceptable salts also include salts formed when anacidic proton present in the parent compound is either replaced by ametal ion (e.g., an alkali metal ion, an alkaline earth metal ion or analuminum ion) or coordinates with an organic base (e.g., ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, morpholine,piperidine, dimethylamine, diethylamine, etc.).

The 2,4-pyrimidinediamine compounds and prodrugs, as well as the saltsthereof, may also be in the form solvates (e.g., hydrates) and N-oxides,as are well-known in the art.

Methods of Synthesis

The 2,4-pyrimidinediamine compounds of the invention may be synthesizedvia a variety of different synthetic routes using commercially availablestarting materials and/or starting materials prepared by conventionalsynthetic methods. Suitable exemplary methods that may be routinelyadapted to synthesize the 2,4-pyrimidinediamine compounds of theinvention are found in U.S. Pat. No. 5,958,935, the disclosure of whichis incorporated herein by reference. Specific examples describing thesynthesis of numerous 2,4-pyrimidinediamine compounds, as well asintermediates therefore, are described in U.S. application Ser. No.10/355,543, filed Jan. 31, 2003 (US2004/0029902A1), the contents ofwhich are incorporated herein by reference. Suitable exemplary methodsthat may be routinely used and/or adapted to synthesize active2,4-substituted pyrimidinediamine compounds can also be found ininternational application Serial No. PCT/US03/03022 filed Jan. 31, 2003(WO 03/063794), U.S. application Ser. No. 10/631,029 filed Jul. 29,2003, international application Serial No. PCT/US03/24087(WO2004/014382), U.S. application Ser. No. 10/903,263 filed Jul. 30,2004 (US2005/0234049), and international application Serial No.PCT/US2004/24716 (WO005/016893), the disclosures of which areincorporated herein by reference. All of the compounds described hereinmay be prepared by routine adaptation of these methods.

Specific exemplary synthetic methods for the 2,4-substitutedpyrimidinediamines described herein are also described in Example 1,below. Those of skill in the art will also be able to readily adaptthese examples for the synthesis of additional 2,4-substitutedpyrimidinediamines as described herein.

An exemplary synthetic route that can be used to synthesize the2,4-substituted pyrimidinediamines compounds of the invention aredescribed in Scheme (I) below. One of ordinary skill in the art couldroutinely adapt this method to synthesize the 2,4-substitutedpyrimidinediamine compounds described herein. As well, in thepublications incorporated herein, numerous alternative synthesisexamples are described in detail.

In one exemplary embodiment, the compounds can be synthesized fromsubstituted or unsubstituted uracils as illustrated in Scheme (I),below:

In Scheme (I), ring A, and the other variables are as defined herein forFormula I. According to Scheme (I), uracil A-1 is dihalogenated at the2- and 4-positions using a standard halogenating agent such as POCl₃ (orother standard halogenating agent) under standard conditions to yield2,4-dichloropyrimidine A-2. Depending upon the R⁸ substituent, inpyrimidinediamine A-2, the chloride at the C4 position is more reactivetowards nucleophiles than the chloride at the C2 position. Thisdifferential reactivity can be exploited to synthesize2,4-pyrimidinediamines A-6 (and ultimately compounds of Formula I, viaregioselective alkylation e.g., if R¹ and R² are not H (as they are inA-6)) by first reacting 2,4-dichloropyrimidine A-2 with one equivalentof amine A-3, yielding 4N-substituted-2-chloro-4-pyrimidineamine A-4,followed by amine A-5 to yield a 2,4-pyrimidinediamine derivative A-6, acompound of Formula I, where R¹ and R² are H.

Typically, the C4 halide is more reactive towards nucleophiles, asillustrated in the Scheme. However, as will be recognized by skilledartisans, the identity of the X substituent may alter this reactivity.For example, when X is trifluoromethyl, a 50:50 mixture of4N-substituted-4-pyrimidineamine A-4 and the corresponding2N-substituted-2-pyrimidineamine is obtained. The regio selectivity ofthe reaction can also be controlled by adjusting the solvent and othersynthetic conditions (such as temperature), as is well-known in the art.

The reactions depicted in Scheme (I) may proceed more quickly when thereaction mixtures are heated via microwave. When heating in thisfashion, the following conditions can be used: heat to 175° C. inethanol for 5-20 min. In a Smith Reactor (Personal Chemistry, Uppsala,Sweden) in a sealed tube (at 20 bar pressure).

The uracil A-1 starting materials can be purchased from commercialsources or prepared using standard techniques of organic chemistry.Commercially available uracils that can be used as starting materials inScheme (I) include, by way of example and not limitation, uracil(Aldrich #13,078-8; CAS Registry 66-22-8); 5-bromouracil (Aldrich#85,247-3; CAS Registry 51-20-7; 5-fluorouracil (Aldrich #85,847-1; CASRegistry 51-21-8); 5-iodouracil (Aldrich #85, 785-8; CAS Registry696-07-1); 5-nitrouracil (Aldrich #85, 276-7; CAS Registry 611-08-5);5-(trifluoromethyl)-uracil (Aldrich #22, 327-1; CAS Registry 54-20-6).Additional 5-substituted uracils are available from GeneralIntermediates of Canada, Inc., Edmonton, Calif. and/or Interchim, Cedex,France, or can be prepared using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

Amines A-3 and A-5 can be purchased from commercial sources or,alternatively, can be synthesized utilizing standard techniques. Forexample, suitable amines can be synthesized from nitro precursors usingstandard chemistry. Specific exemplary reactions are provided in theExamples section. See also Vogel, 1989, Practical Organic Chemistry,Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

Skilled artisans will recognize that in some instances, amines A-3 andA-5 and/or substituent R⁸ on uracil A-1 may include functional groupsthat require protection during synthesis. The exact identity of anyprotecting group(s) used will depend upon the identity of the functionalgroup being protected, and will be apparent to those of skill in theart. Guidance for selecting appropriate protecting groups, as well assynthetic strategies for their attachment and removal, can be found, forexample, in Greene & Wuts, Protective Groups in Organic Synthesis, 3dEdition, John Wiley & Sons, Inc., New York (1999) and the referencescited therein (hereinafter “Greene & Wuts”).

Thus, protecting group refers to a group of atoms that, when attached toa reactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group can beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts, asmentioned above, and additionally, in Harrison et al., Compendium ofSynthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY.Representative amino protecting groups include, but are not limited to,formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”),tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”),2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxylprotecting groups include, but are not limited to, those where thehydroxyl group is either acylated to form acetate and benzoate esters oralkylated to form benzyl and trityl ethers, as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPSgroups) and allyl ethers.

Myriad references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in Scheme (I) areknown in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (Brown II”); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(Brown IV”); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidinediamine synthesis pp. 313-316; aminopyrimidinediamine synthesis pp. 315); Joule, J. A., Mills, K. and Smith,G. F., Heterocyclic Chemistry, 3^(rd) Edition, 1995, Chapman and Hall,London, UK, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4^(th) Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

Example 1

Ethyl4-(3-(5-fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)pyrimidin-2-ylamino)phenyl)piperazine-1-carboxylate,compound number 154 in Table 1, was synthesized according to Scheme (I),using 6-amino-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one and2,4-dichloro-5-fluorouracil (A-2 where R⁸ is F), followed by addition ofethyl 4-(3-aminophenyl)piperazine-1-carboxylate to the corresponding2-chloropyrimidine intermediate (A-4).

¹H NMR (CDCl₃): d 1.14 (t, J=7.2 Hz, 3H), 3.00 (t, J=5.1 Hz, 4H), 3.46(t, J=5.1 Hz, 4H), 4.00 (q, J=7.2 Hz, 2H), 4.47 (s, 2H), 6.55 (dd, J=1.8and 8.4 Hz, 1H), 6.90 (dd, J=1.2 and 7.8 Hz, 1H), 6.98 (t, J=2.1 Hz,1H), 7.04 (d, J=8.7 Hz, 1H), 7.08.

The remaining compounds described herein were made in an analogousmanner.

Utility

The presently disclosed compounds, including the various salts,prodrugs, hydrates and N-oxide forms, and pharmaceutical formulationsthereof, may be used to treat diseases or conditions associated with akinase activity, such as enhanced PLK1 activity. Thus, in a specificembodiment, the 2,4-pyrimidinediamine compounds (and the various formsdescribed herein) may be used to treat disorders associated withabnormal cell proliferation in mammal subjects, including humans. Thecompound may act cytotoxically to kill the abnormally proliferatingcells, or cytostatically to inhibit proliferation without killing thecell.

Methods generally include administering to the subject an amount of acompound of the invention, or a salt, prodrug, hydrate or N-oxidethereof, effective to treat the disorder. In one embodiment, the subjectis a mammal, including, but not limited to, bovine, horse, feline,canine, rodent, or primate. In another embodiment, the subject is ahuman.

A variety of cellular proliferative disorders may be treated with thecompounds of the present invention. In one embodiment, the compounds areused to treat various cancers in afflicted subjects. Cancers aretraditionally classified based on the tissue and cell type from whichthe cancer cells originate. Carcinomas are considered cancers arisingfrom epithelial cells while sarcomas are considered cancers arising fromconnective tissues or muscle. Other cancer types include leukemias,which arise from hematopoietic cells, and cancers of nervous systemcells, which arise from neural tissue. For non-invasive tumors, adenomasare considered benign epithelial tumors with glandular organizationwhile chondomas are benign tumor arising from cartilage. In the presentinvention, the described compounds may be used to treat proliferativedisorders encompassed by carcinomas, sarcomas, leukemias, neural celltumors, and non-invasive tumors.

In a specific embodiment, the compounds are used to treat solid tumorsarising from various tissue types, including, but not limited to,cancers of the bone, breast, respiratory tract (e.g., bladder), brainreproductive organs, digestive tract, urinary tract, eye, liver, skin,head, neck, thyroid, parathyroid, and metastatic forms thereof.

Specific proliferative disorders include the following: a) proliferativedisorders of the breast include, but are not limited to, invasive ductalcarcinoma, invasive lobular carcinoma, ductal carcinoma, lobularcarcinoma in situ, and metastatic breast cancer; b) proliferativedisorders of the skin include, but are not limited to, basal cellcarcinoma, squamous cell carcinoma, malignant melanoma, and Karposi'ssarcoma; c) proliferative disorders of the respiratory tract include,but are not limited to, small cell and non-small cell lung carcinoma,bronchial adenoma, pleuropulmonary blastoma, and malignant mesothelioma;d) proliferative disorders of the brain include, but are not limited to,brain stem and hyptothalamic glioma, cerebellar and cerebralastrocytoma, medullablastoma, ependymal tumors, oligodendroglial,meningiomas, and neuroectodermal and pineal tumors; e) proliferativedisorders of the male reproductive organs include, but are not limitedto, prostate cancer, testicular cancer, and penile cancer f)proliferative disorders of the female reproductive organs include, butare not limited to, uterine cancer (endometrial), cervical, ovarian,vaginal, vulval cancers, uterine sarcoma, ovarian germ cell tumor; g)proliferative disorders of the digestive tract include, but are notlimited to, anal, colon, colorectal, esophageal, gallbladder, stomach(gastric), pancreatic cancer, pancreatic cancer-Islet cell, rectal,small-intestine, and salivary gland cancers; h) proliferative disordersof the liver include, but are not limited to, hepatocellular carcinoma,cholangiocarcinoma, mixed hepatocellular cholangiocarcinoma, and primaryliver cancer; i) proliferative disorders of the eye include, but are notlimited to, intraocular melanoma, retinoblastoma, and rhabdomyosarcoma;j) proliferative disorders of the head and cancers include, but are notlimited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngealcancers, and lip and oral cancer, squamous neck cancer, metastaticparanasal sinus cancer; k) proliferative disorders of the lymphomasinclude, but are not limited to, various T cell and B cell lymphomas,non-Hodgkin's lymphoma, cutaneous T cell lymphoma, Hodgkin's disease,and lymphoma of the central nervous system; l) leukemias include, butare not limited to, acute myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia,and hair cell leukemia, m) proliferative disorders of the thyroidinclude thyroid cancer, thymoma, and malignant thymoma; n) proliferativedisorders of the urinary tract include, but are not limited to, bladdercancer; o) sarcomas include, but are not limited to, sarcoma of the softtissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

It is to be understood that the descriptions of proliferative disordersis not limited to the conditions described above, but encompasses otherdisorders characterized by uncontrolled growth and malignancy. It isfurther understood that proliferative disorders include variousmetastatic forms of the tumor and cancer types described herein. Thecompounds of the present invention may be tested for effectivenessagainst the disorders described herein, and a therapeutically effectiveregimen established. Effectiveness, as further described below, includesreduction or remission of the tumor, decreases in the rate of cellproliferation, or cytostatic or cytotoxic effect on cell growth.

Combination Therapies

The compounds of the present invention may be used alone, in combinationwith one another, or as an adjunct to, or in conjunction with, otherestablished antiproliferative therapies. Thus, the compounds of thepresent invention may be used with traditional cancer therapies, such asionization radiation in the form of gamma-rays and X-rays, deliveredexternally or internally by implantation of radioactive compounds, andas a follow-up to surgical removal of tumors.

In another aspect, the compounds of the present invention may be usedwith other chemotherapeutic agents useful for the disorder or conditionbeing treated. These compounds may be administered simultaneously,sequentially, by the same route of administration, or by a differentroute.

In one embodiment, the present compounds may be used with otheranti-cancer or cytotoxic agents. Various classes of anti-cancer andanti-neoplastic compounds include, but are not limited to, alkylatingagents, antimetabolites, vinca alkyloids, taxanes, antibiotics, enzymes,cytokines, platinum coordination complexes, substituted ureas, tyrosinekinase inhibitors, hormones and hormone antagonists. Exemplaryalkylating agents include, by way of example and not limitation,mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil,ethyleneimines, methylmelamines, alkyl sulfonates (for example,busulfan), and carmustine. Exemplary antimetabolites include, by way ofexample and not limitation, folic acid analogs, such as methotrexate;pyrimidine analog fluorouracil, cytosine arabinoside; purine analogsmercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkyloidsinclude, by way of example and not limitation, vinblastine, vincristine,paclitaxel, and colchicine. Exemplary antibiotics include, by way ofexample and not limitation, actinomycin D, daunorubicin, and bleomycin.An exemplary enzyme effective as anti-neoplastic agents includesL-asparaginase. Exemplary coordination compounds include, by way ofexample and not limitation, cisplatin and carboplatin. Exemplaryhormones and hormone related compounds include, by way of example andnot limitation, adrenocorticosteroids prednisone and dexamethasone;aromatase inhibitors amino glutethimide, formestane, and anastrozole;progestin compounds, such as hydroxyprogesterone caproate andmedroxyprogesterone; and anti-estrogen compounds, such as tamoxifen.

Additional chemotherapeutic agents useful in combination with thepresently disclosed compounds include, without limitation, HDACinhibitors (e.g., MGCD0103 and vorinostat), HSP 90 inhibitors (such as,17-AAG), BCL-2 inhibitors, thalidomide, lenalidomide, mTOR inhibitors(such as, rapamycin, CCI-779), sorafenib, doxorubicine, gemcitabine,dexamethasone, melphalan, proteasome inhibitors (e.g., bortezomib,NPI052), monoclonal antibodies (such as, gemtuzumab, alemtuzumab,ibritumomab tiuxaetan, tositumomab, iodine-131 tositumomab, trastuzumab,bevacizumab, rituximab and anti-TRAIL death receptor antibodies),cytokines (such as interferon-alpha and interferon-gamma, interleukin-2,and GM-CSF), and the like.

These and other chemotherapeutic agents useful in treating cancer aredescribed in the Merck Index, 13th Ed. (O'Neil M. J. et al., ed.) MerckPublishing Group (2001), “Commonly Used Antineoplastic Drugs”, The MerckManuals Online Medical Library For HealthCare Professionals atwww.mercksource.com, and Goodman and Gilmans The Pharmacological Basisof Therapeutics, 10th Edition, Hardman, J. G. and Limbird, L. E. eds.,pg. 1381-1287, McGraw Hill, (1996), each of which are incorporated byreference herein.

Additional anti-proliferative compounds useful in combination with thecompounds of the present invention include, by way of example and notlimitation, antibodies directed against growth factor receptors (forexample, anti-Her2); antibodies for activating T cells (for example,anti-CTLA-4 antibodies); and cytokines such as interferon-alpha andinterferon-gamma, interleukin-2, and GM-CSF.

Formulations and Administration

When used to treat or prevent such diseases, the active compounds may beadministered singly, as mixtures of one or more active compounds or inmixture or combination with other agents useful for treating suchdiseases and/or the symptoms associated with such diseases. The activecompounds may also be administered in mixture or in combination withagents useful to treat other disorders or maladies, such as steroids,membrane stabilizers. The active compounds or prodrugs may beadministered per se, or as pharmaceutical compositions, including anactive compound or prodrug.

Pharmaceutical compositions including the active compounds of theinvention (or prodrugs thereof) may be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making levigating,emulsifying, encapsulating, entrapping or lyophilization processes. Thecompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliarieswhich facilitate processing of the active compounds into preparationswhich can be used pharmaceutically (see Remington's PharmaceuticalSciences, 15.sup.th Ed., Hoover, J. E. ed., Mack Publishing Co. (2003).

The active compound or prodrug may be formulated in the pharmaceuticalcompositions per se, or in the form of a hydrate, solvate, N-oxide orpharmaceutically acceptable salt, as previously described. Typically,such salts are more soluble in aqueous solutions than the correspondingfree acids and bases, but salts having lower solubility than thecorresponding free acids and bases may also be formed.

Pharmaceutical compositions of the invention may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, transdermal,rectal, vaginal, etc., or a form suitable for administration byinhalation or insufflation.

For topical administration, the active compound(s) or prodrug(s) may beformulated as solutions, gels, ointments, creams, suspensions, etc, asare well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, etc., before use.To this end, the active compound(s) may be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate, lecithin). The tablets may be coated by methods wellknown in the art with, for example, sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases such as cocoa butteror other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges including gelatin) may be formulated containinga powder mix of the compound and a suitable powder base such as lactoseor starch.

For ocular administration, the active compound(s) or prodrug(s) may beformulated as a solution, emulsion, suspension, etc, suitable foradministration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specific nonelimiting examples are described in U.S. Pat. No. 6,261,547; U.S. Pat.No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No. 5,800,807; U.S.Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No. 5,521,222;U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat. No.4,882,150; and U.S. Pat. No. 4,738,851.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient may be formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s), Suitable transdermalpatches are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat.No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168; U.S.Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No. 5,164,189;U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat. No.5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No. 4,921,475.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, includemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

Effective Dosages

The active compound(s) or prodrug(s) of the invention, or compositionsthereof will generally be used in an amount effective to achieve theintended result, for example in an amount effective to treat or preventthe particular disease being treated. The compound(s) may beadministered therapeutically to achieve therapeutic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated and/or eradication or amelioration ofone or more of the symptoms associated with the underlying disorder suchthat the patient reports an improvement in feeling or condition,notwithstanding that the patient may still be afflicted with theunderlying disorder. Therapeutic benefit also includes halting orslowing the progression of the disease, regardless of whetherimprovement is realized.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, the severity of the indicationbeing treated and the age and weight of the patient, the bioavailabilityof the particular active compound, etc. Determination of an effectivedosage is well within the capabilities of those skilled in the art.

Effective dosages may be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals may be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC50 of the particular compound as measured in anin vitro assay, such as the in vitro assays described in the Examplessection. Calculating dosages to achieve such circulating blood or serumconcentrations talking into account the bioavailability of theparticular compound is well within the capabilities of skilled artisans.For guidance, the reader is referred to Fingi & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pp. 1-46, latest edition, Pagamonon Press, andthe references cited therein.

Initial dosages may also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Dosage amounts will typically be in the range of from about0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may behigher or lower, depending upon, among other factors, the activity ofthe compound, its bioavailability, the mode of administration andvarious factors discussed above. Dosage amount and interval may beadjusted individually to provide plasma levels of the compound(s) whichare sufficient to maintain therapeutic or prophylactic effect. Forexample, the compounds may be administered once per week, several timesper week (e.g., every other day), once per day or multiple times perday, depending upon, among other things, the mode of administration, thespecific indication being treated and the judgment of the prescribingphysician. In cases of local administration or selective uptake, such aslocal topical administration, the effective local concentration ofactive compound(s) may not be related to plasma concentration. Skilledartisans will be able to optimize effective local dosages without undueexperimentation.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) may be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) LD50/ED50effect is the therapeutic index (LD50 is the dose lethal to 50% of thepopulation and ED50 is the dose therapeutically effective in 50% of thepopulation). Compounds(s) that exhibit high therapeutic indices arepreferred.

Kits

The compounds and/or prodrugs described herein may be assembled in theform of kits. In some embodiments, the kit provides the compound(s) andreagents to prepare a composition for administration. The compositionmay be in a dry or lyophilized form, or in a solution, particularly asterile solution. When the composition is in a dry form, the reagent mayinclude a pharmaceutically acceptable diluent for preparing a liquidformulation. The kit may contain a device for administration or fordispensing the compositions, including, but not limited to syringe,pipette, transdermal patch, or inhalant.

The kits may include other therapeutic compounds for use in conjunctionwith the compounds described herein. In some embodiments, thetherapeutic agents are other anti-cancer and anti-neoplastic compounds.These compounds may be provided in a separate form, or mixed with thecompounds of the present invention.

The kits will include appropriate instructions for preparation andadministration of the composition, side effects of the compositions, andany other relevant information. The instructions may be in any suitableformat, including, but not limited to, printed matter, videotape,computer readable disk, or optical disc.

EXAMPLES

The ability of compounds described herein to inhibit PLK1 wasdemonstrated in a biochemical PLK1 ELISA assay using an artificial PLK1substrate and in a cellular assay using cultured human chronicmyelogenous leukemia K562 cells overexpressing the natural PLK1substrate, CDC25C protein. Inhibition of PLK1 was measured byquantifying phosphorylation of PLK1 substrates using chemiluminescentand fluorogenic probes. The protocols for these assays are providedbelow.

The IC₅₀ values for tested compounds are presented in Table 1, both forthe biochemical non-cellular ELISA assay, and for the cellular assay.

Many compounds exhibit IC₅₀ values of less than 10 μM in biochemicalELISA assay. These compounds include compound Nos. 3, 4-6, 15-21, 23-30,32-56, 95-97, 101, 107-111, 114-116, 120, 122, 125, 127-134, 157, 161,167-169, 173, 183, 188, 189, 191 and 196. Of these, many compoundsexhibit IC₅₀ values of less than 0.01 μM in biochemical ELISA assay:compound Nos. 5, 6, 17, 19, 25, 26, 36, 40, 42, 48, 49, 50, 51, 55, 122,127-130, 134, 157, and 168-169.

For many compounds inhibition of Aurora B kinase was measuredsimultaneously with PLK1 inhibition in a cellular assay. For manycompounds high PLK1/Aurora B selectivities were observed (for examplerepresentative compounds exhibited a significantly lower IC₅₀ for PLK1than IC₅₀ for Aurora B). For example, in one aspect the disclosed PLK1inhibitors inhibit PLK1 at least about 1.2-fold more potently than theyinhibit Aurora B, such as from about 1.2-fold to about 1000-fold, fromabout 2-fold to about 500-fold or from about 10-fold to about 100-foldmore potently.

In Vitro PLK1 ELISA Assay

I. Preparation of Assay Plates.

Costar 96-well black or white solid flat high binding plates (FisherScientific, Catalog No. 07-200-591) were coated with Neutravidin(Pierce, Catalog No. 31000) using the following protocol. A 0.01 mg/mLsolution of Neutravidin in 1× Phosphate Buffered Saline (“PBS”,Cellgro/Mediatech, Catalog No. 21-040-CV) was added to each well (100μL/well) and was incubated for 18-24 hours at 4° C. The plates were thenwashed with 1× Phosphate Buffer Saline—Tween (“PBST”, Calbiochem,Catalog No. 524653) buffer using a plate washer. The plates were treatedwith bovine serum albumin (“BSA”, Sigma, Catalog No. A7906) to blocknon-specific binding sites, by adding a 2% BSA solution in 1×PBST bufferto each well (100 μL/well) and incubating the plates for 1 hour at roomtemperature. The plates were then washed with 1×PBST buffer using aplate washer.

2. PLK1-Catalyzed Phosphorylation Reaction

An aqueous buffer solution A having the following composition wasprepared:

20 mM HEPES (Cellgro/Mediatech, Catalog No. 25-060Ci), pH 7.2;

5 mM MgCl₂ (Sigma, Catalog No. M2393);

2 mM MnCl₂.4H₂O (EM Biosciences, Catalog No. MX0185-2);

0.01% Brij-35 (Sigma, Catalog No. B4184);

1 mM Dithiothreitol (“DTT”, Fluka, Catalog No. B4184).

Next, the substrate solution B was prepared by adding 2.6 μL of 10 mMATP (Sigma, Catalog No. A7699) and 6.4 μL of the 1 mM PLK1 substrate,CHK2-derived peptide Biotin-SSLETVSTQELYSIP (custom synthesized atAnaspec) SEQ ID: No. 1, to 4691 μL of the buffer solution A. Theconcentration of the ATP in solution B is 5.44 μM (1.36×); theconcentration of the PLK1 substrate in solution B is 1.36 μM (1.36×).

Compound solutions C of varying concentrations for each compound wereprepared by dissolving each compound in dimethylsulfoxide (DMSO, Sigma,Catalog No. D2650) to varying concentrations, followed by adding 2 μL ofeach solution to 38 μL of the buffer solution A, thereby forming 10×compound solutions in 5% DMSO.

A PLK1 solution D was prepared by adding 8.44 of 100 μg/mL PLK1 (CellSignalling, Catalog No. 7728) to 1392 μL of the buffer solution A,thereby forming 0.6 μg/mL (6×) PLK1 solution.

The aqueous 1.36× substrate solution B was added to each well (44μL/well) resulting in binding of the substrate to the plate viabiotin/neutravidin interaction. Then 10× compound solutions C for eachtested compound at each tested concentration were added to each well (6μL/well). Next, 6×PLK1 solution D was added to each well (10 μL/well).

The final concentrations of tested compounds in each well were 10 μM,3.3 μM, 1.1 μM, 0.36 μM, 0.12 μM, 0.04 μM, 0.014 μM, and 0.005 μM.

The obtained reaction mixtures were incubated in the wells for 45minutes at room temperature, allowing PLK1-catalyzed phosphorylation ofthe substrate to proceed. The plates were then washed with 1×PBSTsolution using a plate washer, such that the bound phosphorylated orunphosphorylated substrate remains attached to the wells upon washing.

3. Plate Development

The washed plates were developed by treating the plates with a primaryantibody that is specific for the phosphorylated substrate, followed bytreatment with a secondary antibody that is specific for the primaryantibody, and that is capable of catalyzing a reaction that results in achemiluminescent readout. The chemiluminescent readout was used toquantify the substrate phosphorylation, and, consequently, to determineIC₅₀ values for PLK1 inhibition, and was measured using a luminometer(Perkin Elmer/Wallac plate reader). The plate development protocol isdescribed below.

A mixed antibody solution E was prepared by adding 1 μL of the primaryantibody, rabbit p-CHK2(T68) (Rockland, Catalog No. 401280), and 1 μL ofthe secondary antibody, HRP-goat anti-rabbit IgG (Jackson ImmunoresearchCatalog No. 111-035-003) to 10000 μL of 0.1% BSA in 1×PBST buffer.

An ELISA substrate solution F was obtained from Thermo Scientific(Supersignal ELISA Pico Catalog No. 37069) and contained 3,000 μL ofsolution A (Stable Peroxide Solution, Prod #1859677), 3,000 μL ofsolution B (Luminol Enhancer Solution, Prod #1859676) and 6,000 μL ofwater.

After the plates were washed, a mixed antibody solution E was added toeach well (100 μL/well) and the plate was incubated for 60 minutes atroom temperature. The plate was then washed with 1×PBST buffer solutionusing a plate washer. Next, an ELISA substrate solution was added toeach well (100 μL/well) and chemiluminescence at each well was measuredusing Perkin Elmer/Wallac plate reader. IC50 values for the testedcompounds were then determined based on quantification ofchemiluminescence.

4. Results

The IC₅₀ data for the tested compounds are reported in Table 1.

Cellular PLK1 Assay

1. Culturing of K562 Cells

Human chronic myelogenous leukemia K562 cells (American Tissue CultureCollection) overexpressing CDC25C, were grown in Growth Medium havingthe following composition: Iscove Dulbecco's Modified Eagle's Medium(“Iscove DMEM”, Mediatech/Cellgro, Cat. #10-013-CV), 10% Fetal BovineSerum (“FBS”, SAFC Biosciences, Cat. #12106-500M), and 1%penicillin/streptomycin (“pen-strep”, Mediatech/Cellgro, Cat.#30-002-CI). The cells were plated in 96 well round bottom tissueculture plates (Fisher, Costar* Cell Culture plates, Cat. #07-200-95) at100,000 cells per 50 μL of Growth Medium per well. Nocodazole (Sigma,Cat. #M1404) was added to the growth media to arrest the cells in the G2or M phase, at 333 nM concentration. The cells were incubated withnocodazole for 18 hours at 37° C. prior to addition of tested compounds.

2. Treatment of Cells with the Tested Compounds

Solutions of tested compounds in DMSO at different concentrations wereprepared using serial dilutions. Each compound was tested at 8concentration points, 10 μM, 3.3 μM, 1.1 μM, 0.37 μM, 0.12 μM, 0.04 μM,0.014 μM, 0.005 μM, duplicate replicates.

Two controls were performed: “DMSO alone” control in which nocodazoleand DMSO were present but no compounds were added, and “nocodazolealone” control, in which only nocodazole was present, but neither DMSOnor compounds were added.

The solutions of compounds were prepared by diluting 10 mM compound 1:1in DMSO (5 μL 10 mM compound and 5 μL DMSO), followed by 1:3 serialdilutions of compound in DMSO performed by diluting 3 μL of higherconcentration compound solution serially into 6 μL DMSO to give 3-folddilutions. Next, 3 μL of each compound solution at each concentrationwas transferred to 750 μL of Growth Medium. In “DMSO alone” control 3 μLof DMSO alone was added to 750 μL of Growth Medium.

After the diluted compounds were mixed well in the Growth Medium, 50 μLof each compound solution in DMSO/Growth Medium was transferred to eachwell of the 96-plate containing cells in 50 μL of GrowthMedium/Nocodazole.

The cells and compounds were incubated for 120 minutes at 37° C., in anatmosphere containing 5% CO₂.

3. Fixation and Permeabilization of the Cells

After the cells were incubated with compounds, the cells were spun downat 1,000 rpm for 5 minutes at 4° C. and supernatants were removed byflicking the plates. Cells were then washed with 200 μl of ice cold PBS,spun down again and supernatants removed. Cells were then fixed andpermeabilized by addition of 100 μL/well of Fixation andPermeabilization Solution (1× buffer provided in BD BiosciencesCytofix/Cytoperm™ Fixation/Permeabilization kit, Cat. #554714) andincubation for 20 minutes at room temperature. The fixative was thenremoved by centrifugation (5 minutes at 2,000 rpm), and plates wereflicked to remove the fixative and washed twice, each time with 200μL/well BD Perm/Wash buffer (10× concentrate provided in BD BiosciencesCytofix/Cytoperm™ Fixation/Permeabilization kit, Cat. #554714, 1× bufferprepared by dilution in distilled H2O).

4. Staining

Cells were spun down at 1,000 rpm for 5 minutes at 4° C. Supernatantswere removed by flicking the plates. A solution of a primary antibodyspecific for cdc25cp-Ser198 was prepared by diluting Rabbit cdc25c(Ser198) antibody (Cell Signaling, #9529L) 1:50 in a FluorescenceActivated Cell Sorting (“FACS”) Buffer (2% FBS in PBS). The cell pelletswere resuspended in 50 μL of the primary antibody solution. 50 μL ofFACS buffer was added to unstained controls. Staining was allowed toproceed overnight at room temperature.

The plates were then washed by addition of 200 μL of FACS Buffer to eachwell, were centrifuged and the supernatant was removed.

Next, 50 μL/well of a secondary antibody anti rabbit PE (R-Phycoerythrinconjugated goat F(ab′)2 Anti-Rabbit IgG (Biosource™), Invitrogen, Cat noALI4407) was added to each cell pellet at 1:1,000 dilution with FACSbuffer and was incubated for 1 hour at room temperature.

Plates were washed with 200 μL of FACS buffer, were centrifuged and wereresuspended in 80 μL of FACS buffer for analysis.

The plates were analyzed using Automatic Micro-Sampling System (AMS) onthe FACSCalibur™ flow cytometer (BD Biosciences), collecting 10,000cells per well.

5. Results

IC₅₀ values for the assayed compounds were determined based on thefluorescent readouts obtained in flow cytometric analysis. The resultsare presented in Table 1.

Cellular Aurora B Assay

Cellular Aurora B assay can be performed separately or concurrently withthe PLK1 assay. In one example Aurora B assay was performed concurrentlywith the PLK1 assay. The cells were grown, treated with the testedcompounds and fixed as described above. During staining in addition tocdc25cp-Ser198 primary antibody (for phosphorylated PLK1 substrate) aprimary antibody for Aurora B substrate, mouse phospho-histone H3antibody (Cell Signaling #9706L) was used (1:100 dilution in FACSbuffer). The cells were resuspended in 50 μL of diluted primaryantibodies solution mixture. After staining and washing as describedabove, secondary antibodies were added. In addition to anti rabbit PEsecondary antibody, an anti mouse APC secondary antibody(Allophycocyanin crosslinked goat anti mouse antibody, Invitrogen, Cat.#M30005) was used (50 μL/well of secondary antibody mixture). Themixture was diluted with FACS buffer and incubated as described above.The plates were processed as described above and were analyzed using theAMS on the FACSCalibur™ flow cytometer (BD Biosciences), collecting10,000 cells per well.

Although various details have been omitted for clarity's sake, variousdesign alternatives may be implemented. Therefore, the present examplesare to be considered as illustrative and not restrictive, and theinvention is not to be limited to the details given herein, but may bemodified within the scope of the appended claims.

1. A method of treating a disease or condition associated with PLK1catalytic activity in a mammal, wherein the method comprisesadministering to the mammal a therapeutically effective amount of acompound according to Formula I, or a pharmaceutically acceptable salt,solvate, prodrug or N-oxide thereof,

wherein: Y¹ is O; Z¹ is CH or N; A is phenyl or a 6-membered heteroaryl;R¹ is H; R² and R³ are each, independently of one another, H, (C1-C6)alkyl optionally substituted with one or more of the same or differentR¹¹ groups, (C3-C8) cycloalkyl optionally substituted with one or moreof the same or different R¹¹ groups, (C4-C11) cycloalkylalkyl optionallysubstituted with one or more of the same or different R¹¹ groups,(C5-C10) aryl optionally substituted with one or more of the same ordifferent R¹¹ groups, (C6-C16) arylalkyl optionally substituted with oneor more of the same or different R¹¹ groups, 2-6 membered heteroalkyloptionally substituted with one or more of the same or different R¹¹groups, 3-8 membered cycloheteroalkyl, optionally substituted with oneor more of the same or different R¹¹ groups, 4-11 memberedcycloheteroalkylalkyl, optionally substituted with one or more of thesame or different R¹¹ groups, 5-10 membered heteroaryl optionallysubstituted with one or more of the same or different R¹¹ groups or 6-16membered heteroarylalkyl optionally substituted with one or more of thesame or different R¹¹ groups; R⁴ and R⁵ are each, independently of oneanother, H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, halogen,(C1-C6) haloalkoxy, (C1-C6) aminoalkyl or (C1-C6) hydroxyalkyl; or,alternatively, R⁴ and R⁵, taken together with the carbon atom to whichthey are bonded, form a spirocycloalkyl or a spirocycloheteroalkyl, or,alternatively, R⁴ and R⁵, taken together with the carbon atom to whichthey are bonded, form a C═O group; R⁶ and R⁷ are each, independently ofone another, H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy,halogen, (C1-C6) haloalkoxy, (C1-C6) aminoalkyl or (C1-C6) hydroxyalkyl;or, alternatively, R⁶ and R⁷, taken together with the carbon atom towhich they are bonded, form a spirocycloalkyl or a spirocycloheteroalkylor, alternatively, R⁶ and R⁷, taken together with the carbon atom towhich they are bonded, form a C═O group; R⁸ is H, halo, (C1-C6) alkyloptionally substituted with one or more of the same or different R¹¹groups, (C1-C3) haloalkyloxy, —OR^(d), —SR^(d), —NR^(c)R^(c), (C1-C3)haloalkyl, —C(O)OR^(d), —CN, —NC, —OCN, —SCN, —NO or —NO₂; two R⁹, takentogether with the nitrogen atom to which they are bonded, form a 4- to8-membered monocyclic cycloheteroalkyl, 6- to 10-membered bridgedbicyclic cycloheteroalkyl, or 6- to 12-membered bridged tricycliccycloheteroalkyl, wherein each may optionally be substituted with one ormore of the same or different R¹¹ groups, and wherein the substituted orunsubstituted mono-, bi- or tricyclic cycloheteroalkyl includes at leasttwo nitrogen atoms; each R¹⁰ is independently R¹¹ or alternatively, twoR¹⁰ on vicinal carbons, taken together with the carbons to which theyare bonded, form a ring fused to A, where the ring fused to A is a 5- to8-membered cycloalkyl, a 5- to 8-membered cycloheteroalkyl, 5- to6-membered aryl or a 5- to 6-membered heteroaryl, each optionallysubstituted with one or more of the same or different R¹¹ groups; eachR¹¹ is independently H, R^(e), R^(b), R^(e) substituted with one or moreof the same or different R^(a) and/or R^(b), —OR^(e) substituted withone or more of the same or different R^(a) and/or R^(b), —SR^(e)substituted with one or more of the same or different R^(a) and/orR^(b), —C(O)R^(e) substituted with one or more of the same or differentR^(a) and/or R^(b), —N(R^(a))R^(e) where R^(e) is substituted with oneor more of the same or different R^(a) and/or R^(b), —S(O)₂R^(e)substituted with one or more of the same or different R^(a) and/orR^(b), —N(R^(a))—S(O)₂R^(e) where R^(e) is substituted with one or moreof the same or different R^(a) and/or R^(b), —B(OR^(a))₂,—B(N(R^(c))₂)₂, —(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(a))₂)_(m)—R^(b),—S—(C(R^(a))₂)_(m)—R^(b), —O—(C(R^(b))₂)_(m)—R^(a),—N(R^(a))—(C(R^(a))₂)_(m)—R^(b), —O—(CH₂)_(m)—CH((CH₂)_(m)R^(b))R^(b),—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—O—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—N((C(R^(a))₂)_(m)R^(b))₂,—S—(C(R^(a))₂)_(m)—C(O)N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—N(R^(a))—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b),—N(R^(a))—C(O)—(C(R^(a))₂)_(m)—C(R^(a))(R^(b))₂ or—N(R^(a))—(C(R^(a))₂)_(m)—C(O)—N(R^(a))—(C(R^(a))₂)_(m)—R^(b); eachR^(a) is independently H, deuterium, (C1-6)alkyl, (C3-8)cycloalkyl,(C4-11)cycloalkylalkyl, (C6-10)aryl, (C7-16)arylalkyl, 2-6 memberedheteroalkyl, 3-10 membered heteroalicyclyl, 4-11 memberedheteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 memberedheteroarylalkyl; each R^(b) is independently ═O, —OR^(a),—O—(C(R^(a))₂)_(m)—OR^(a), (C1-3)haloalkyloxy, —OCF₃, ═S, —SR^(a),═NR^(a), ═NOR^(a), —N(R^(c))₂, halo, —CF₃, —CN, —NC, —OCN, —SCN, —NO,—NO₂, ═N₂, —N₃, —S(O)R^(a), —S(O)₂R^(a), —SO₃R^(a), —S(O)N(R^(c))₂,—S(O)₂N(R^(c))₂, —OS(O)R^(a), —OS(O)₂R^(a), —OSO₃R^(a),—OS(O)₂N(R^(c))₂, —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(c))₂,—C(NR^(a))—N(R^(c))₂, —C(NOH)—R^(a), —C(NOH)—N(R^(c))₂, —OC(O)R^(a),—OC(O)OR^(a), —OC(O)N(R^(c))₂, —OC(NH)—N(R^(c))₂, —OC(NR^(a))—N(R^(c))₂,—N(R^(a))—S(O)₂H, —[N(R^(a))C(O)]_(n)R^(a), —[N(R^(a))C(O)]_(n)OR^(a),—[N(R^(a))C(O)]_(n)N(R^(c))₂ or —[N(R^(a))C(NR^(a))]_(n)—N(R^(c))₂; eachR^(c) is independently R^(a), or, alternatively, two R^(c) are takentogether with the nitrogen atom to which they are bonded to form a 3 to10-membered heteroalicyclyl or a 5-10 membered heteroaryl which mayoptionally include one or more of the same or different additionalheteroatoms and which is optionally substituted with one or more of thesame or different R^(a) and/or R^(d) groups; each R^(d) is ═O, —OR^(a),—OCF₃, ═S, —SR^(a), ═NR^(a), ═NOR^(a), —N(R^(a))₂, halo, —CF₃, —CN, —NC,—OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a), —S(O₂)R^(a), —SO₃R^(a),—S(O)N(R^(a))₂, —S(O)₂N(R^(a))₂, —OS(O)R^(a), —OS(O)₂R^(a), —OSO₃R^(a),—OS(O)₂N(R^(a))₂, —C(O)R^(a), —CO₂R^(a), —C(O)N(R^(a))₂,—C(NR^(a))N(R^(a))₂, —C(NOH)R^(a), —C(NOH)N(R^(a))₂, —OCO₂R^(a),—OC(O)N(R^(a))₂, —OC(NR^(a))N(R^(a))₂, —[N(R^(a))C(O)]_(n)R^(a),—(C(R^(a))₂)_(n)—OR^(a), —N(R^(a))—S(O)₂R^(a), —C(O)—(C1-6)haloalkyl,—S(O)₂—(C1-6)haloalkyl, —OC(O)R^(a), —O(C(R^(a))₂)_(m)—OR^(a),—S(C(R^(a))₂)_(m)—OR^(a), —N(R^(a))—(C1-6)haloalkyl, —P(O)(OR^(a))₂,—N(R^(a))—(C(R^(a))₂)_(m)—OR^(a), —[N(R^(a))C(O)]_(n)OR^(a),—[N(R^(a))C(O)]_(n)N(R^(a))₂, —[N(R^(a))C(NR^(a))]_(n)N(R^(a))₂ or—N(R^(a))C(O)(C1-6)haloalkyl; or, alternatively, two R^(d), takentogether with the atom or atoms to which they are attached, combine toform a 3-10 membered partially or fully saturated mono or bicyclic ring,optionally containing one or more heteroatoms and optionally substitutedwith one or more R^(a); each R^(e) is independently (C1-6)alkyl,(C3-8)cycloalkyl, (C4-11)cycloalkylalkyl, (C6-10)aryl, (C7-16)arylalkyl,2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 memberedheteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 memberedheteroarylalkyl; each m is independently an integer from 1 to 3; andeach n is independently an integer from 0 to 3; provided the compound isnot:N4-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-yl)-5-fluoro-N2-[3-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;4-{3-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid methyl ester;N4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-[3-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;4-{3-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid ethyl ester;1-(4-{3-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone;6-{5-Fluoro-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;6-{2-[3-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;4-{3-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid ethyl ester;6-{5-Fluoro-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one;6-{2-[3-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one;4-{3-[5-Fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid ethyl ester;N4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;N2-[3-Chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-N4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-pyrimidine-2,4-diamine;N4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine;4-{4-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid ethyl ester;1-(4-{4-[4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone;4-{4-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid ethyl ester;4-{4-[5-Fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid ethyl ester;6-{5-Fluoro-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;6-{5-Fluoro-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one;6-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;4-{4-[4-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid methyl ester;4-{4-[5-Fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamino)-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid methyl ester; or6-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-fluoro-pyrimidin-4-ylamino}-4H-pyrido[3,2-b][1,4]oxazin-3-one.2. The method of claim 1, wherein the compound is selected from thegroup of compounds presented in Table 1, characterized by an IC₅₀ ofless than 10 μm in a cell-based PLK1 inhibition assay.
 3. The method ofclaim 1, wherein two R⁹ are taken together with the nitrogen atom towhich they are bonded form a 6- to 10-membered bridged bicyclic or a 6-to 12-membered bridged tricyclic group, each optionally substituted withone or more of the same or different R¹¹.
 4. The method of claim 3,wherein the 6- to 10-membered bridged bicyclic group is [3.3.3],[3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2] or [2.2.1].
 5. The method ofclaim 3, wherein the bridged bicyclic or bridged tricyclic group is

wherein R^(f) is R^(a), —S(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d) or—C(O)NR^(c)R^(c); and wherein each R^(g) is independently H, halogen or(C1-C6) alkyl.
 6. The method of claim 1, wherein the compounds hasFormula II

wherein: two R⁹ taken together with the nitrogen atom to which they arebonded form a 6- to 10-membered bridged bicyclic group optionallysubstituted with one or more of the same or different R¹¹, wherein thebridged bicyclic group contains at least two annular nitrogen atoms; R¹⁰is defined as in claim 1; R⁸ is H, (C1-C3) alkyl, (C1-C3) alkoxy,halogen, —CN, —NO₂, (C1-C3) haloalkyl, —C(O)OR^(d) or (C1-C3)haloalkyloxy; R² is H, (C1-C6) alkyl, (C3-C6) cycloalkyl or (C4-C6)cycloalkylalkyl; R³ is as defined in claim 1; R⁶ and R⁷ are each,independently of one another, H, halo or (C1-C6) alkyl, or,alternatively, R⁶ and R⁷ are taken together with the carbon atom towhich they are bonded to form an optionally substituted spirocycloalkylor an optionally substituted spirocycloheteroalkyl.
 7. The method ofclaim 6, wherein the compound has Formula III:


8. The method of claim 6, wherein the compound has Formula IV:


9. The method of claim 6, wherein the compound has Formula V:


10. The method of claim 6, wherein the compound has Formula VI:

wherein the dashed line represents a bivalent linker, wherein thebivalent linker, together with the oxygens and annular carbon atoms towhich the oxygens are bonded, forms a 5- to 8-membered cycloheteroalkylring.
 11. The method of claim 6, wherein the compound has Formula VII:


12. The method of claim 1, wherein the compound has Formula XIII:

wherein: two R⁹ taken together with the nitrogen atom to which they arebonded form a 6- to 10-membered bridged bicyclic group optionallysubstituted with one or more of the same or different R¹¹, wherein thebridged bicyclic group contains at least two annular nitrogen atoms; R¹⁰is defined as in claim 1; R⁸ is H, (C1-C3) alkyl, (C1-C3) alkoxy,halogen, —CN, —NO₂, (C1-C3) haloalkyl, —C(O)OR^(d) or (C1-C3)haloalkyloxy; R² is H, (C1-C6) alkyl, (C3-C6) cycloalkyl or (C4-C6)cycloalkylalkyl; R³ is as defined in claim 1; and R⁶ and R⁷ are each,independently of one another, H, halo or (C1-C6) alkyl, or,alternatively, R⁶ and R⁷ are taken together with the carbon atom towhich they are bonded to form an optionally substituted spirocycloalkylor an optionally substituted spirocycloheteroalkyl.
 13. The method ofclaim 12, wherein the bridged bicyclic group is

wherein R^(f) is R^(a), —S(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d) or—C(O)NR^(c)R^(c); and wherein each R^(g) is independently H, halogen or(C1-C6) alkyl.
 14. The method of claim 12 wherein the compound has oneof the following formulae:

wherein the dashed line represents a bivalent linker, wherein thebivalent linker, together with the oxygens and annular carbon atoms towhich the oxygens are bonded, forms a 5- to 8-membered cycloheteroalkylring.
 15. The method of claim 1 wherein the compound has Formula XXIV:


16. The method of claim 1 wherein the compound has one of the followingformulae:

wherein R⁹ and R¹⁰ are as defined in claim 1; R⁸ is H, (C1-C3) alkyl,(C1-C3) alkoxy, halo, —CN, —NO₂, (C1-C3) haloalkyl, —C(O)OR^(d) or(C1-C3) haloalkyloxy; R² is H, (C1-C6) alkyl, (C3-C6) cycloalkyl or(C4-C6) cycloalkylalkyl; R³ is as defined in claim 1; and R⁶ and R⁷ areeach, independently of one another, H, halo or (C1-C6) alkyl, or,alternatively, R⁶ and R⁷ are taken together with the carbon atom towhich they are bonded to form an optionally substituted spirocycloalkylor an optionally substituted spirocycloheteroalkyl.
 17. The method ofclaim 16 wherein the two R⁹ groups are taken together with nitrogen towhich they are bonded to form:

wherein R^(f) is R^(a), —S(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d) or—C(O)NR^(c)R^(c).
 18. The method of claim 16 wherein at least one R¹⁰ isin an ortho position, N(R⁹)₂ is in a meta position, or both.
 19. Themethod of claim 16 wherein at least two R¹⁰ groups are attached tovicinal carbons and occupy ortho and meta positions.
 20. The method ofclaim 1, wherein the disease or condition is a neoplasm.